After high school, Strange entered pre-med at a New York college. Later, home on vacation for his nineteenth birthday, Strange went swimming with Donna, who suffered a cramp and drowned. Finding her body after a desperate search, Strange felt a sense of personal failure that eroded his medical idealism. After earning his medical degree in record time, he entered a five-year residency at New York Hospital, where his rapid success made him arrogant. When his mother Beverly died near the end of his residency, a bereaved Strange grew distant from his work. His talent was unaffected, though, and he became a wealthy, celebrated neurosurgeon before he turned thirty. His egotism made him cold and callous, interested only in high fees. He saved the life of injured United Nations translator, Madeleine Revell; following a romance and proposal, she left him due to his increasingly materialist nature. Two years after Beverly's death, her husband Eugene fell ill; unable to face another family death, Stephen refused to visit his deathbed. A few days later, an outraged Victor berated Stephen for his apparent lack of grief, then rushed from Strange's apartment into the path of an oncoming car. Blaming himself, Strange placed Victor's body in cold storage, half-hoping that future breakthroughs could revive him.

Circa 1963, Strange was in a car accident that severely damaged the nerves in his hands, ending his surgical career. Too vain to accept positions as a consultant or assistant, Strange sought a cure and pursued every available treatment, legitimate or not, soon depleting his fortune; in months he was reduced to a derelict, performing shady medical procedures that barely paid his bar tabs. After hearing rumors of the mystical Ancient One, a desperate Strange pawned his last possessions for a ticket to the East and found the Ancient One's Tibetan palace. At first annoyed when the Ancient One refused to cure him, Strange was later astonished to see the sorcerer attacked by mystic forces. Upon learning that the Ancient One was Earth's magical defender and that the attack on him came from his pupil Mordo, Strange tried to warn him, but Mordo mystically prevented Strange from doing so. For the sake of the Ancient One and the world, Strange acted unselfishly for the first time in years, vowing to learn magic himself so he could counter Mordo and his ilk. He offered himself as a disciple to the Ancient One, who accepted, having known of Mordo's treachery all along. The Ancient One spent years instructing Strange in the art of sorcery, teaching him how to tap the innate mystic powers of both himself and the world around him, as well as how to invoke the power of awesome entities, or Principalities, who resided in their own realms, most notably the three benign beings known as the Vishanti. A few years after Strange's arrival, Mordo left to seek greater power, and would often clash with Strange in the future. Strange's guilt over his earlier mistakes weighed heavily upon him over the years, and not all of his early recollections can be trusted.

While the Fantastic Four's debut heralded an upsurge of superhuman activity in recent years, Strange remained aloof from New York's many super heroes at first. The powerful Asgardian god Loki later tricked Strange into covertly attacking Loki's heroic foster brother, Thor; however, Strange soon pierced the deception and united with Thor to drive off Loki. Soon afterward, a clash with Mordo led Strange to encounter the young Spider-Man, who helped Strange rescue several people from a mystic dimension and convinced him to remove their memory of the traumatic experience, even though this caused them to forget Spider-Man's heroism as well. Impressed by Spider-Man's bravery and altruism, Strange came to regard him as a friend, and the two unlikely allies have teamed up many times over the years.

Strange soon faced the Dreaded Dormammu, ruler of the Dark Dimension and one of the Ancient One's oldest foes. Sensing the Ancient One's declining power, Dormammu plotted anew to invade the Earth dimension and challenged Strange to a mystic duel in the Dark Dimension. While there, Strange was approached by Clea, a novice mystic and daughter of Dormammu's sister Umar, although few knew her parentage at the time. Clea sought to prevent the duel, fearful that her home dimension would be devastated by the Mindless Ones if its ruler fell, but Strange would not yield. Although Dormammu vastly out powered Strange, their duel drained his energies enough to weaken the barrier which contained the Mindless Ones. Strange, unwilling to endanger the Dark Dimension's denizens, lent Dormammu enough power to restore the barrier. Enraged by his own weakness, Dormammu felt honor-bound to spare Strange, who bargained with him to spare both the Earth dimension and Clea, whom he found very attractive; however, Dormammu swore vengeance and became one of Strange's most implacable enemies.

Shortly after this, Strange openly joined several super heroes in battling the powerful mutate Sundown. He became a special consultant to prominent super-teams like the Fantastic Four, the X-Men and the Avengers. Months after attending the wedding of Reed and Sue Richards, Strange was reunited with Clea, who returned his love and came to live with him in New York. Later, following an extradimensional ordeal, he was forced to change his appearance in order to cross the barrier to Earth; he altered his traditional attire and added a full-face mask, perhaps in imitation of his super-hero allies. Upon his return, Strange retained this appearance to preserve his anonymity but later carelessly revealed his real name to a crowd while fighting Nightmare. Eternity, the universal embodiment whom Strange was aiding at the time, altered all documents and memories on Earth, changing the name of "Stephen Strange" to "Stephen Sanders" to allow Strange a private persona once more.

Weeks later, Strange returned to action when Baron Mordo tried to kill him. Aided by the Ancient One, Strange reclaimed his sorcerer role and defeated Mordo, while the Ancient One, for reasons of his own, reversed Eternity's spell, restoring the name "Stephen Strange" to the world's records and memories. When the Nameless One returned shortly thereafter, Strange resumed his non-masked attire and again recruited Namor and the Hulk to fight alongside him. The three heroes later fought other threats and were soon joined by the alien Silver Surfer. This quartet formed the core of the heroic Defenders team, becoming friends despite their differences.

Strange soon clashed with powerful demon servants of Shuma-Gorath, a vast extradimensional entity who had menaced Earth thousands of years ago and now sought to return via the mind of the Ancient One himself. At his mentor's prompting, Strange slew the Ancient One, preventing Shuma-Gorath's passage. The Ancient One's physical death made him one with Eternity, and Strange became Sorcerer Supreme, guardian of the entire universe. Heavily burdened by his new responsibilities and seeking the solace of family, Strange tried and failed to revive his brother Victor using spells from the Book of the Vishanti, not realizing he was reading the Vampiric Verses, imbuing Victor with the potential for resurrection as a vampire.

Strange continued to share adventures with the Defenders, and over the months the informal team's ranks expanded to include the Asgardian Valkyrie, the winged millionaire Nighthawk, the happy-go-lucky Hellcat, and others. Strange's time with the team forced him to face more non-mystical foes, such as the mutant Magneto, the alien Nebulon the Celestial Man, the subversive Sons of the Serpent and the bizarre masterminds called the Headmen. Strange's sanctuary often served as Defenders headquarters, and their camaraderie, plus the love of Clea, gave Strange a welcome change from his customary solitude.

Manipulated by the trans-temporal sorcerers called the Creators, the Ancient One's spirit offered Strange a chance to become one with the universe, but Strange refused and was stripped of the title and power of Sorcerer Supreme. Shortly afterward, Strange battled the Creators, thwarting their reality-reshaping plans by defeating their ally, the cosmic In-Betweener. With their deception revealed, the Ancient One restored Strange's former status. Although Strange's adventure took mere days from his perspective, weeks apparently passed on Earth; who, if anyone, held the post of Sorcerer Supreme during these weeks is unrevealed.

Months later, Strange and the three other senior Defenders parted ways after a cosmic hoax by the mysterious alien Tribunals convinced them their alliance was destined to cause cosmic tragedy. Next allied with a band of vampires hunters against Dracula, Strange cast the Montesi Formula spell taken from the ancient magic tome the Darkhold. This spell destroyed virtually all vampires within the Earth dimension; however, unknown to Strange, the spell's energy washed over the forgotten Victor Strange, where its power combined unpredictably with Strange's earlier spell.

Meanwhile, Clea had returned to the Dark Dimension to lead the rebellion against its current ruler, Umar, whom she soon learned was her mother. Strange helped Clea ascend to her home universe's throne, but, bound by their respective responsibilities, the couple regretfully separated. Strange next found those very responsibilities challenged by the evil extraterrestrial Urthona, who coveted the role of Sorcerer Supreme. A desperate Strange destroyed his own collection of mystic artifacts and tomes to deny Urthona their power; unknown to Strange, his collection was in fact rescued by Agamotto, one of three Principalities who formed the Vishanti.

With the removal of Strange's artifacts, various occult threats that had been repelled by their power over the millennia broke free, leaving Strange to face them with reduced power. Accompanied by the extradimensional novice mystic Rintrah, Strange encountered the Ancient One's old rival Kaluu, who offered to teach him life-draining black magic as a defense against the returning forces; Strange reluctantly accepted. Strange's black magic ventures culminated in a rematch with Shuma-Gorath, which ended with the demon seemingly destroyed and Strange little better-off, but Strange eventually recovered and returned home. Shortly thereafter, he visited the Dark Dimension and married Clea, who came to live with him on Earth, ruling her kingdom from afar. Strange took Rintrah as his new apprentice, and a surreal encounter with Agamotto restored his seemingly lost artifacts and tomes.

Strange faced a far more unexpected part of his past when his brother Victor revived as the first of a new breed of vampire. Victor fell under the sway of sorceress Marie LaVeau, who sought to blackmail Strange into reciting the Vampiric Verses, nullifying the effects of the Montesi Formula. Strange instead banished the Vampiric Verses page from the Earth dimension, but Marie LaVeau used Victor as a template to duplicate the spell, making it possible for long-destroyed vampires to reappear. Unable to undo this threat, Strange and Clea were next drawn into a war between Dormammu and Umar for rule of the Dark Dimension; ultimately Umar reclaimed the throne, leaving Clea in exile with Strange. Strange next allied himself with several super heroes against the mad Titan Thanos, who used the near-omnipotent Infinity Gauntlet to eradicate half of the universe's population before Earth's heroes defeated him and reversed the effect.

As Clea sought allies to regain the Dark Dimension, Strange formed alliances of his own by manipulating the formation of the Midnight Sons, a loose-knit group of supernatural heroes, including those who had helped him invoke the Montesi Formula, destined to confront ancient evils. During Clea's absence, he briefly tutored the young sorcerer Augustyne Phyffe, who ultimately chose to abandon sorcery. After sharing leadership of Earth's heroes against the Magus during the Infinity War, Strange teamed with Namor, the Hulk, and the Silver Surfer to battle Shanzar, the invading Sorcerer Supreme of another dimension (by now, Strange had long since discovered the Tribunals' hoax and knew it was safe for the senior Defenders to reunite).

Meanwhile, the Principalities of various mystic realms faced the War of the Seven Spheres, a cataclysmic clash with opposing entities that was expected to last five thousand years. Several of them, including the Vishanti, attempted to enlist allies such as Strange, but Strange refused to abandon his earthly duties and, being no match for the godlike Principalities, renounced the use of their mystic energies. Thus stripped of much of his power, Strange was ill-prepared to face a vastly enhanced Dormammu, who had manipulated Clea's deposal of Umar so that he could again rule the Dark Dimension. Strange recruited the Hulk, the Silver Surfer, and the Ghost Rider (Dan Ketch) to aid him in repelling Dormammu, who retained control of the Dark Dimension despite Strange's victory, and Clea remained there to lead the new resistance. Strange sought out Immortalis in hopes of curing Victor, but was refused due to the temporary nature of the cure. Shortly afterward, Rintrah was seemingly slain destroying a dangerous talisman, and Strange, after placing Rintrah's body in stasis pending potential revival, took as a new apprentice Kyllian Kell, a youth empowered by Celtic gods. Strange also began periodically gathering informal teams of heroes as "Secret Defenders" to face threats he could not handle alone.

Strange's life was further complicated by Salomé, a winged member of the mysterious Blood race and allegedly the first Earth-born Sorcerer Supreme over 20,000 years ago. With Strange's power still low, Salomé easily reclaimed her title; however, she cared little for humanity and began gathering followers to help her rule the Earth. Desperate for more power, Strange secluded himself in a pocket dimension, from which he dispatched two magical constructs based upon himself: Vincent Stevens, who built a fortune with which to develop so-called technomagick, and a being called Strange, who fought alongside the Midnight Sons and gathered objects of mystic power throughout the world. Unable to spare the energy to lead the Secret Defenders, Dr. Strange abruptly forced this responsibility upon another former student of the Ancient One, Doctor Druid, who served as best he could yet was ultimately unable to maintain the operation.

Dr. Strange had barely finished enhancing his sorcery when Stevens and Strange rebelled against him; in the resulting clash, Stevens was apparently destroyed, and Strange went to the Dark Dimension, where he merged with the rebellion's Nobel as Paradox, working beside Clea. Using elemental magic to defeat Salomé, Dr. Strange assumed a short-lived younger form and briefly adopted a more violent persona to shut down illegal operations engineered by Stevens. However, Dr. Strange's plans were interrupted when the Vishanti once again demanded his service in the War of the Seven Spheres. Unwilling to risk yet another loss of power, Strange complied.

Although Strange spent five thousand years fighting for the Vishanti against the mysterious Trinity of Ashes, he returned to Earth with little sign of physical age, only a few months after he had departed, his memories of the war largely suppressed; again, it is not known if anyone carried out Strange's duties in his absence. Having exhausted his typical powers, Strange sought new ones through the use of unpredictable Catastrophe Magic, which he later supplemented with so-called Chaos Magic; however, Strange later claimed there was no such thing as Chaos Magic, confusing matters considerably. In any event, Strange eventually regained the patronage of the Principalities, his powers restored to their height. Dormammu used the mutant Jonathon White and Strange's ally Topaz against the mage, but Strange drove off his enemy and magically guided another surgeon to save Topaz from Dormammu's attack.

Another sort of status quo returned when the extradimensional techno-mage Yandroth, an old foe of both Strange and the Defenders, unleashed destructive forces upon the Earth. Strange, Namor, Hulk and the Surfer united against Yandroth, but time had made them less compatible. When Yandroth seemingly perished, he used Earth's magical energy to bind the quarrelsome quartet with a spiteful curse that would force them together against all future threats to Earth, regardless of their other concerns. Other Defenders alumni lent their aid in coping with this situation, and Strange, although irritated by Yandroth's curse, was not untouched by the renewed camaraderie of his fellow heroes. However, the curse magnified the anger and egos of the four senior Defenders until they became mentally unstable and, as the Order, sought to end all threats to the Earth by taking control of it. Several other heroes, including Clea, fought them, and the energies unleashed by the battle were harnessed to resurrect Yandroth in a powerful new form. Shocked back to their senses by this development, the four Defenders stopped fighting, which reduced Yandroth to human form. Yandroth was defeated and imprisoned.

Shaken by his misuse of power and position, Strange cut himself off from his super-hero allies, even becoming aloof from his longtime friend Spider-Man. When the idealistic mystic Topaz became Strange's fifth known disciple, he held her at an emotional distance and, when she disobeyed him in the aftermath of a mystic threat, he dismissed her. Although Strange continues to defend the Earth dimension and to assist fellow heroes as needed, his old arrogance has resurfaced, and his ultimate role in recent upheavals within the superhuman community remains to be seen.