Under a cloud of increasing anti-mutant sentiment, Professor Xavier created a safe haven at his Westchester mansion where he could train young mutants to use their powers for the betterment of mankind. Aided by F.B.I. agent Fred Duncan, Xavier spent months recruiting his early students (code-named Cyclops, Iceman, Angel, Beast and Marvel Girl), dubbing them "X-Men" because each possessed an "extra" ability normal humans lacked. The X-Men made their public debut by thwarting Magneto's seizure of the Cape Citadel missile base. The U.S. military was grateful, and the youngsters were initially regarded as heroes. Magneto would battle the X-Men repeatedly over the years, sometimes leading his Brotherhood of Evil Mutants. The X-Men also battled such threats as the immovable Blob, the untouchable Unus, the alien Lucifer, the savage Swamp Men, the enigmatic Stranger, the unstoppable Juggernaut, and the giant mutant-hunting Sentinel robots.

The arrogant mutated human Mimic briefly joined the team before Xavier secretly went into hiding. Requiring seclusion to prepare for a forthcoming invasion of Earth by the alien Z'nox, Xavier had the shape-shifting mutant Changeling impersonate him in order to supervise the X-Men in his absence; however, the Changeling "Xavier" died heroically in battle against the subterranean Grotesk. Of the X-Men, only Marvel Girl knew that Xavier was still alive, though she was sworn to secrecy. Duncan had the X-Men disband briefly, but the team had regrouped by the time Xavier finally came out of hiding, leading them in repelling the Z'nox with the aid of the Fantastic Four. Joined by Polaris and Havok, the heroes befriended Avia of the Savage Land's Nhu-Gari race, and fought the likes of African mutant Deluge (alongside young future member Storm), the mutant slave-runner Krueger, the criminal Dazzler (Angel's uncle, Burt Worthington), the telepathic alliance known as the Promise, the Inhuman Yeti, and the Secret Empire.

When the sentient island Krakoa captured most of his students, Xavier hastily assembled a second squad of X-Men. Traveling the world, he recruited Nightcrawler in Germany, Wolverine in Canada, Banshee in Ireland, Storm in Kenya, Sunfire in Japan, Colossus in Russia, and Thunderbird in America. Led by Cyclops, these all-new, all-different X-Men were able to rescue their predecessors. Except for Cyclops, the previous members all quit the expanded team. Sunfire also left the group, and Thunderbird died battling Count Nefaria and his Ani-Men during an attempted takeover of the N.O.R.A.D. facility in Cheyenne Mountain.

When the U.S. government unleashed new-model Sentinels that imprisoned Jean Grey and several other X-Men on a space station, the team escaped to Earth in a shuttle through a lethal solar-radiation storm. Dying from radiation, Jean was touched by the cosmic Phoenix Force, which replicated Jean's form and absorbed a portion of her consciousness. Guiding the shuttle to a crash-landing, the Phoenix Force secretly placed the real Jean in stasis within a cocoon-like pod at the bottom of Jamaica Bay, then took her place in the X-Men. The X-Men subsequently battled the Juggernaut, Magneto, Emperor D'Ken of the intergalactic Shi'ar Empire, the eccentric assassin Arcade, the prehistoric mutant Sauron, Alpha Flight, the reality-altering Proteus, and the Hellfire Club. The Club's probationary member Jason Wyngarde (Mastermind) mentally manipulated the Phoenix, who was rapidly corrupted by her own vast power and, as a result, transformed into Dark Phoenix. Ultimately, Jean's psyche resurfaced and convinced the Phoenix Force to sacrifice itself to save the universe. Believing Jean to be dead, Cyclops quit the team, leaving Storm to lead them in his absence.

The X-Men soon welcomed more new members, including Kitty Pryde, Rogue, and Rachel Summers. When the X-Men were believed dead after an encounter with the alien Brood, Xavier formed a new team of students dubbed the New Mutants. After the X-Men returned, Xavier continued to mentor both teams. The New Mutants even served temporarily as X-Men to save the team from interdimensional media mogul Mojo.

The real Jean Grey eventually revived and was reunited with the original X-Men members. Together they established X-Factor, supposedly a business dedicated to hunting and capturing dangerous mutants, but secretly a group formed to protect, recruit and mentor mutants in need of guidance, like Xavier before them. At the same time, the X-Factor group moonlighted as an openly mutant super-hero team, the X-Terminators. Their ranks already scattered and depleted after battles with the likes of Mr. Sinister's Marauders, the X-Men seemingly died battling the Adversary in Dallas, but they secretly survived and relocated to the Australian Outback, battling threats such as the cyborg Reavers, the Master Mold, and Nanny and her Orphan-Maker. While seeking the missing X-Men, Forge and Banshee helped form an ad-hoc team of X-Men to defend Muir Island from the Reavers. This team then fell under the thrall of the psychic Shadow King, and it took the combined efforts of the X-Men and X-Factor to defeat him. Afterwards, the members of X-Factor rejoined the X-Men which then split into two teams, Blue and Gold.

When Magneto nearly killed Wolverine by forcibly extracting the Adamantium implants from his skeleton, Xavier retaliated by telepathically lobotomizing Magneto; but Xavier paid a high price for this action. Tainted by Magneto's essence, Xavier unwittingly created the evil psionic entity Onslaught, which seemingly slew most of New York's major super heroes before being defeated. The heroes eventually returned, but not before Xavier was arrested for his part in the creation of Onslaught. Incarcerated, Xavier was interrogated by the hybrid Sentinel Bastion, who used the information he gained to launch an assault on the X-Men under the guise of the government-sponsored Operation: Zero Tolerance program. After the program was shut down, Xavier was forced to flee from his own mutant-locating computer Cerebro, which had become a sentient nanotech construct due to Bastion's machinations. Trying to realize Xavier's dream and fulfill its mutant-recruitment programming, Cerebro created solid holographic amalgamations of mutants in Xavier's files, then set about "recruiting" them to join a new team of X-Men with itself as their "founder". Cerebro's plan was foiled by the true X-Men, and it was ultimately stopped after Xavier caused it to overload.

Magneto soon resurfaced, holding the planet hostage with its own magnetic field, and convinced the world's leaders to grant him sovereignty over Genosha, an island nation near South Africa where humans once enslaved mutants. At first forced to cope with civil war and the effects of the lethal Legacy Virus, Magneto gained the might of a unified nation when a cure for the mutant plague was released into the atmosphere. Magneto proclaimed his intended dominance over mankind, standing ready to unleash an entire nation of mutates upon the planet. With the aid of a hastily-assembled interim team, the X-Men narrowly averted the would-be conqueror's ultimate offensive.

When Xavier and the X-Men were publicly outed as mutants by Xavier's genetic twin, Cassandra Nova, the Xavier Institute was overwhelmed with an influx of young mutants seeking safety and education. To cope with the large student body, Xavier recruited several new faculty members into the Institute, including former Alpha Flight member Northstar and a reformed Juggernaut. Xavier also formed the X-Corporation, a global search-and-rescue unit for oppressed mutants. The X-Corporation boasts headquarters around the world, with numerous mutants from the various splinter teams rallying to join the cause.

Following an all-out assault on Manhattan by a mutant posing as Magneto, Xavier left the X-Men to help the true Magneto rebuild Genosha after it was devastated by a Sentinel attack. Cyclops and Emma Frost became co-headmasters of the Institute and reorganized the X-Men into three separate teams, leading one team themselves in an effort to improve the X-Men's standing with the public. A second team was led by Cyclops' brother Havok, while the third, the X-Treme Sanctions Executive led by Storm, acted as a global mutant police force until its license was revoked in the wake of "M Day".