Following the apparent death of mutant superhero Jean Grey (FAMKE JANSSEN) while battling evil mutant Magneto (IAN McKELLEN) and his followers, the surviving X-Men are trying to get on with their lives. That includes headmaster Professor Charles Xavier (PATRICK STEWART) who resumes teaching new students, such as Kitty Pryde (ELLEN PAGE), while Storm (HALLE BERRY) and Wolverine (HUGH JACKMAN) clash over how to train them in simulated battles.
But not everyone is happy, including Cyclops (JAMES MARSDEN), Jean Grey's boyfriend who's still reeling from her demise, while young mutant Rogue (ANNA PAQUIN) is still frustrated that her deadly powers mean she can't even hold hands with her boyfriend and fellow mutant, Bobby (SHAWN ASHMORE).
But there's a greater concern for the world of mutants as Dr. Hank McCoy (KELSEY GRAMMER) of the Department of Mutant Affairs reports that Alcatraz-based Worthington Labs has developed a serum that can turn mutants back into humans. It seems that researcher Warren Worthington II (MICHAEL MURPHY) was so upset that his son, Warren Worthington III (BEN FOSTER), was a winged mutant that he looked for such a cure and found it in the form of young boy Leech (CAMERON BRIGHT) whose very presence nullifies any mutant powers.
Concerned that The President (JOSEF SOMMER) and his assistant Trask (BILL DUKE) will use the cure to rid the world once and for all of every mutant, Magneto and former Xavier student Pyro (AARON STANFORD) free a number of other mutants to help them defeat the cause. Among them is longtime Magneto ally, the shape-shifting Mystique (REBECCA ROMIJN) and the indestructible Juggernaut (VINNIE JONES). As his name would indicate, Multiple Man (ERIC DANE) can create multiple versions of himself, while the speedy Callisto (DANIA RAMIREZ) can track any mutant.
Once he realizes that Jean Grey has risen from the dead with her powerful, inner alter-ego, The Phoenix, making her the most powerful mutant ever, Magneto uses Callisto to find and recruit her. As that band of bad mutants make their way toward Alcatraz to destroy Leech and the cure derived from him, Wolverine and the other mutants set out to stop them.