When Jean "Phoenix" Grey's mind is taken control of by Mastermind and the Inner Circle, she sacrifices herself to protect the world. A year has passed since Jean's death, and the X-Men have since disbanded and the Xavier Institute closed. When Charles Xavier receives word that a mutant named Hisako Ichiki has been kidnapped, he sends out a call to Storm, Wolverine and Beast. After being informed they are to fly to the Tōhoku region of Japan, where Xavier's psychic abilities can't seem to reach, Wolverine and Storm go to talk to Cyclops, who has been brooding since Jean's death, in order to convince him to join them.

The X-Men arrive in Tōhoku and talk with Hisako's parents concerning her disappearance, learning that several other mutants have gone missing over the past few years. As the X-Men suspect this to be the work of the U-Men, a group of humans that harvest mutant organs in order to produce counter measures against mutants, they soon learn yet another mutant boy has gone missing. As they split up to investigate, Beast realizes the call was bait to lure them into a trap, and they are soon attacked by the U-Men's robots. After defeating the robots, the X-Men regroup and head to an abandoned hospital which is thought to be the U-Men's base. There, they find the missing boy being pumped with chemicals and transform into a huge monster. Despite learning his body is beyond biological repair, Cyclops is reluctant to fight against him, but is eventually forced to kill him in order to save his allies. Before passing away, the boy asks the X-Men to save the others. As they move on, they discover a laboratory where Hisako is being kept, along with another woman that Cyclops saw during his battle with Jean.

With Wolverine and Cyclops holding back their urges to kill Emma, the X-Men release Hisako and Emma, the latter of which denies having any part in that battle a year ago, since she had apparently already left the Inner Circle by then. As Hisako awakens, it is revealed that Emma was hired to be her tutor, since the Xavier Institute had ceased activity, and was captured when she went to Japan to search for Hisako. After defeating a group of cyborgs, the X-Men arrive at an operating room, where they are confronted by one of the U-Men, who uses the data collected on the X-Men to gain an advantage. As he targets Emma, Hisako's mutant powers awaken, using her mind's energy to create a powerful armor which defeats him. However, her powers soon go out of control, but Emma manages to calm her down. As the other U-Men escape, the X-Men manage to free the other children, but just then, the U-Men thought killed launches an attack at Hisako, forcing Emma to rush to protect her.

Emma's desire to protect Hisako causes her to develop a secondary mutation protecting them from the attack, whilst the other X-Men kill the attacking U-Man. After Hisako is reunited with her parents, she and Emma agree to go to the Xavier Institute to receive a vaccine to prevent 'David Haller Syndrome' in secondary mutations. En route back to New York, the Blackbird is attacked by a mutant suffering from DHS which Wolverine defeats. Emma recognizes him as a student from the Inner Circle's preparatory school. Upon returning to the Institute, Beast tries to investigate the boy's condition, but he shrivels up and dies. Beast concludes that the cause of his secondary mutation was not due to experimentation but some other stimulus. As Beast performs checks on Emma, Xavier reveals Cerebro is still being blocked from Tōhoku. With Emma's secondary mutation on the same level as the boy, though hers is deemed harmless, Xavier suspects something is still going on in Tōhoku which is causing these mutations.

As Hisako starts training to use her powers, she finds herself at odds with Cyclops who still doesn't trust Emma and shows a dislike to Xavier recruiting her as part of the X-Men. As the other X-Men discuss the possibility of Mastermind having a hand in Jean's death, Cyclops pits Hisako in a real battle against him, pushing her to go berserk with her powers so she can take control of it. Noticing Hisako lacking self-confidence, Emma agrees to have Xavier read her mind, revealing her childhood and her affiliation with the Inner Circle and her reason for leaving, also proving she was not involved with the battle with Jean. As a result, Cyclops apologizes to Emma whilst Hisako strives to learn from her mistakes. As the X-Men prepare to leave for Tohoku with the vaccines, Emma questions Xavier about a woman named Yui Sasaki which she saw when their minds were linked.

As the X-Men arrive back in Tohoku, Hisako's parents inform them of strange things that happened whilst they were away. As Beast administers the vaccine to various mutants, some of which have already started going through secondary mutation, the other X-Men investigate the abnormalities, including a strange volcanic area by the river and a twisted metal bridge. As the X-Men fly towards the center of the area in which mutants have been affected by secondary mutation, Emma starts hearing a painful noise and the Blackbird is shot down. Upon landing, the X-Men witness the Blackbird being attacked by living snow before they are attacked by another U-Man, who uses their powers against them. However, Beast manages to find its weak point, allowing the others to defeat him. They spot he has a mutant detection device before he self-destructs himself. As a snowstorm kicks in, the X-Men finds shelter in a lodge owned by Yui Sasaki, the woman Xavier mentioned, who was the headmaster of a mutant institute Hisako went to when she was little.

As the X-Men talk to Yui, Emma suspects she may be lying about her relation to Xavier. Yui later contacts Xavier, revealing he has a son named Takeo that had died. As Wolverine, Storm and Beast investigate the phenomenon which ensnared their Blackbird, they are confronted by two mutants who escape after setting off an avalanche. As Hisako goes to find Yui concerning some irritation on her right hand, Emma asks to dive into Cyclops' mind in order to quell his hesitation. Meanwhile, Yui is mysteriously attacked.

Yui's experimental drug fails to stop the mutant gene from awakening.

The X-Men best Hedgehog and follow Marsh and Mastermind deeper into Yui's laboratory.

Marsh traps Emma Frost, Hisako and Yui; Neuron subdues Wolverine and Beast; Hisako reflects on a mutant who went into hiding.

Professor X summons the X-Men to protect humanity as the world is on the brink of destruction.

On the brink of world destruction, Charles reaches out to all the X-Men, other mutants and heroes around the world asking them to support one another and protect humanity.