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A mysterious huge explosion destroys the X-Mansion at the moment that Wolverine was leaving. Professor X and Jean Grey are mysteriously missing, and perhaps gone for good, causing the X-Men to disband. Beast is examining the remains of the explosion and finds out that Professor X was the target. However, one year later, an anti-mutant government agency called the Mutant Response Division (or M.R.D. for short) hunt Wolverine and arrest a family that helped him. This causes him to go after them with the help of Beast. Inside the jail, they free all the mutants, including Dust, Boom Boom, and Pyro. In the end, Wolverine decides to find the other X-Men and fight the MRD.

Beast and Wolverine manage to bring Shadowcat and Iceman back the X-Men, while some such as Cyclops, Colossus, and Rogue, do not wish to return. Rogue takes up the cause of the Brotherhood of Evil Mutants, who have sinister plans to attack Senator Kelly. Kelly's plan is to push forth a Mutant Registration Act. Meanwhile, Angel's father, Warren Worthington, is funding the M.R.D., building anti-mutant robots. The remaining X-Men seek to stop the Brotherhood, despite Kelly's stance on mutants. At the end of the episode, we see that it was Rogue who had betrayed the X-Men.

With help from Angel, the X-Men are able to move back into the rebuilt mansion. Forge has been brought to the team to repair Cerebro and the Blackbird. The telepathic Emma Frost, the beautiful former headmistress of the Massachusetts Academy, requests to join the X-Men in order to help find Professor X. Wolverine is suspicious at in the beginning but reluctantly agrees, believing that Emma only has intentions to take control of Cerebro. Emma Frost is able to locate Professor X in Magneto's controlled mutant nation of Genosha. Now with Cyclops back in action, Wolverine leads the X-Men on a mission into the enemy territory in order to retrieve their lost mentor.

Professor X shows Wolverine a future vision of a destroyed Africa and reveals that Storm is the one who destroyed it. It isn't long before the Shadow King tries to take control of Storm's body. At the end of the episode Storm rejoins the X-Men.

Magma is being chased by the M.R.D. In the middle of a road she turns to a burning lava-like being and the cars suddenly stop around her. Wolverine rescues Magma from the M.R.D. and uses an ability-inhibitor collar built by Forge to help control her mutant abilities. When Wolverine asks for the collar back, she is reluctant to take it off but finally does so. Meanwhile, Dr. Sybil Zane hires Gambit to steal that collar from the X-Men for Senator Kelly and it is up to Wolverine to get it back. Gambit attacks Wolverine in his laboratory with kinetically charged cards, he admits to Wolverine that he has been hired for cash, but Wolverine sets his money on fire and offers him double the amount, if he helps discovering whom he is working for. In the end Wolverine manages to get back the collar.

There is news that Nightcrawler was seen on a ship traveling to Genosha with other mutants, so the X-Men try to find him. Meanwhile, Nightcrawler and the other travellers (including Squidboy, Vindaloo, Network, Shatter, Pixie, Feral, and other mutants) are intercepted by "pirates", who really are Spiral and the Reavers, looking for fighters within the pool of high level mutants to take them to Mojo. In the deep night the pirates attack the ship carrying the mutants to Genosha and the crew is worried about the change of course towards Genosha. Nightcrawler defeats the pirates. Wolverine, Beast, Shadowcat, and Forge come to pick him up and take him back to the mansion. But he declines saying he wants to make sure the mutants make it safely to Genosha.

In a sequel to the Hulk Vs, Nick Fury asks Wolverine a "favor" to once again fight against the Hulk in exchange for keeping the X-Men's real identities and the reality behind the Xavier school secret. However, Wolverine finds that there is more than Fury is letting on when Wolverine and the Hulk encounter the real monster terrorizing the Canadian Rockies and attacking the S.H.I.E.L.D. agents dispatched there: the Wendigo. Wolverine keeps the Wendigo monsters busy while Banner searches for the cure. At the end, Wolverine gets revenge on Fury by awakening the Hulk claiming "Hulk wanted to thank you too."

Professor Xavier warns the X-Men about an impeding event that wipes half the mutant population: Nitro will self-detonate in Genosha. The Brotherhood "rescue" Nitro from a government prison against his will and use Psylocke to control him, planning to use him as a weapon. The X-Men chase the Brotherhood in order to prevent Genosha's destruction.

In the future, Professor X is captured by the Sentinels. Along with Domino, Bishop, Hellion, Marrow, and others, the Professor plans to break free from his captors. Meanwhile, Wolverine and the other X-Men search Bolivar Trask's old lab for any info on Master Mold.

The ship Nightcrawler was on arrives in Genosha. There, the Scarlet Witch tours Nightcrawler around so that he can see the wonders Magneto has done. Then, Nightcrawler and the Scarlet Witch start to fall head-over-heels romantically madly in love. However, Dust informs Nightcrawler that things in Genosha aren't what they seem. Meanwhile, Mystique breaks into the X-Mansion and apparently has a past link with Wolverine. Dust reveals to Nightcrawler that Magneto imprisons some mutants in an underground dungeon, before getting caught herself. Nightcrawler summons all of his teleportation abilities to get back to the X-Mansion, only to be captured by Mystique.

Wolverine goes to recover part of his past as a Weapon X agent and finds Maverick's daughter. As Weapon X doesn't want Logan to remember anything about his time in their organization, they send Sabretooth to deal with him. Meanwhile, Rogue finds it hard to adjust to her new settings as she overhears Quicksilver getting a mission from Magneto. When she finally visits the X-Mansion, she is upset to learn that Wolverine is not there.

Cyclops, still lamenting the loss of his dear beloved Jean Grey, believes Mister Sinister has taken her. He fights the Marauders with the help of the X-Men until he realizes Jean is not with them. An amnesiac Jean is revealed to be alive and well in a hospital, supposedly having been in a coma.

Magneto sends his Acolytes to break several mutants out of prison. Meanwhile, the X-Men fight the Brotherhood and find Tildie Soames (a young mutant whose nightmares can manifest into monsters) is attacking the city while still in a coma-like state. Rogue's true purpose in joining the Brotherhood is revealed and she has to make a choice between her old friends and her new ones. Meanwhile, Bobby sums up the courage to ask Kitty out on a date.

Mystique calls Wolverine to warn him that Maverick's daughter, Kristie, is in danger. The two of them infiltrate Weapon X and have to fight Maverick and Sabretooth - and some old ghosts from the past as well.

Mojo takes Nightcrawler and the Scarlet Witch from Genosha to put them in a TV show, while also forcing Wolverine to attack them by controlling his mind. Spiral and the Reavers also appear.

In the twenty-year future, Professor Xavier and his new X-Men fight the Sentinels and come across Polaris, who lives alone and traumatized in a destroyed Genosha. Charles learns how Genosha was destroyed and how Polaris was the only survivor. In the present, Wolverine, Forge and Shadowcat infiltrate an MRD base to investigate the Master Mold, only for the former two to get caught which led to the Wolverine-type Sentinels that the future X-Men just evaded.

Wolverine comes back to the mansion to discover that the Silver Samurai had captured the X-Men. Having been defeated by Wolverine a few years ago, the Samurai forces Wolverine to fight him to death and regain his honor, in order to officially become a Yakuza clan leader. The odds are stacked against Wolverine as the rules of the duel restrict him from using his claws, and he has long since forgotten how to fight with a sword.

The MRD starts hunting mutants without warning, forcing the X-Men to strike back. Angel joins the X-Men and tries to destroy the artificial intelligence/multi-agent system, Mastermold, accompanied by the Brotherhood who were betrayed by Magneto. However, the dystopian future still exists and Mastermold had transferred itself to a damaged Sentinel.

After furiously snapping at his father on the development of a so-called "cure" for mutants, Angel's wings are severely damaged at the hands of the MRD and are ordered to be cut off. However, Mr. Sinister then makes him a proposal that will change his life forever, transforming Angel into Archangel and with even stronger angelic wings.

During a battle with Juggernaut, Cyclops is distracted by a vision of Jean and Juggernaut defeats and escapes the X-Men. Emma proposes to erase all memories of Jean from Scott's mind and he accepts. When Emma enters his mind, she looks at all his memories. The truth behind the explosion is revealed to be Jean transforming into the almighty, cosmic Phoenix.

Cyclops and Wolverine inform Professor X of Emma's discovery about the source of the explosion. Fearing that Jean may be responsible for the destruction of Genosha, Professor X and his team of future X-Men try to uncover information on the event from Master Mold's original detention center. The only seen way to get past the Sentinel guards is to send the group's reprogrammed Sentinel "Rover" on a "Kamikaze" attack run. While Bishop has no problem with it, Marrow has developed an incredible bond to Rover and refuses to give him up.

Gambit arrives on Genosha under the orders of Senator Kelly to steal Magneto's helmet as a provocation of war, as well as cripple Genosha's resources. Much to the dismay of the Scarlet Witch, Gambit charms Polaris who unknowingly aids him in his task. Wolverine and Nightcrawler head to Genosha to prevent Gambit from stealing Magneto's helmet. Though Gambit seems attracted to Polaris, he leaves her at the end with Magneto's helmet. Polaris gets infuriated and disables Gambit's get away and takes the helmet back. Gambit is then stranded in the ocean. Through the intervention of the X-Men, Magneto and Senator Kelly reach an understanding about their impending war and the dystopian future.

An amnesic Jean uses her incredibly strong and powerful telepathic and telekinetic abilities while at the hospital, which allows Emma to locate her using Cerebro. Emma and Scott go to the hospital and attempt to take Jean back to the mansion when Archangel intercepts Scott and Jean and takes them to Mr. Sinister where he extracts their genetic codes, stating that combined they will create the very strongest and most powerful force in the world. Before his men can dispose of Scott and Jean, the X-Men arrive and save them. Later, Emma appears to double-cross the X-Men and the Hellfire Club arrives to take an unconscious Jean. Meanwhile, Mister Sinister gives Jean and Scott's DNA to his master, Apocalypse.

Suspecting Emma's hand in Jean's abduction, Wolverine places her in a holding cell. Emma is later freed by Cyclops, who trusts her to find Jean. Apparently, the Hellfire Club had become aware that the Phoenix Force had possessed Jean and supposedly wants to extract the divine Phoenix Force from her mind and use its infinite and limitless power and strength for their own ends. Meanwhile, Magneto hatches a plot against the human race, having replaced Senator Kelly with Mystique to start an attack on Genosha. In the future, the Professor is apprehended by Sentinels, who have replicated Cerebro to find all mutants in the world.

Emma discovers the Hellfire Club's true motivation for using the Phoenix Force, and fights to free Jean alongside Cyclops. In Genosha, Magneto's plan comes to fruition as Sentinels ravage the island, providing just cause for Magneto's war against humanity. Accordingly, Magneto reprograms the Sentinels to attack humans. In the future Professor X and the future X-Men are freed by Wolverine, and together they take up a fight against Master Mold. 

The X-Men, MRD and S.H.I.E.L.D. fight against Magneto's Sentinels. Meanwhile, the Inner Circle reveals to Scott that Emma and the Stepford Cuckoos were the ones responsible for setting in motion the events that would lead to the destruction of the mansion, Xavier's twenty-year coma and the eventual extraction of the Phoenix Force from Jean's mind and body. Upon the successful transmission of the Phoenix Force from Jean and into the bodies of all five Stepford Cuckoos, the possessed girls are then instructed by Sebastian Shaw to destroy the Sentinels, the X-Men and Genosha, an action which was completely unknown to Emma whose initial plan was to both locate and destroy the cosmic entity before it could reach maturity and bring forth unparalleled global destruction. In the wake of her regretable actions, Emma attempts to redeem herself in the eyes of the X-Men, especially Scott, by ultimately sacrificing herself in order to successfully destroy the Phoenix Force entity. In the aftermath of the carnage, Magneto is banished from Genosha for his radical actions while his eldest daughter, Wanda, assumes authority over the destroyed island and its inhabitants, alongside her sister Lorna, in an attempt to rebuild from the demolished remains of her father's mistakes. From the future, Xavier informs the X-Men that their mission was a success and that the bleak, sentinel-run world has now been avoided. However, there is a new and far more formidable future that has taken its place: the Age of Apocalypse.