<P> Izzie makes a treatment error that endangers the life of a patient, and is fired from the hospital's surgical program . Believing Alex is partially to blame, she writes him a Dear John letter and leaves . Izzie later learns that Alex was not responsible for her lost job, and returns to make amends with him, but Meredith informs her that Alex is moving on . Izzie informs Alex that she no longer has cancer . Although he is pleased, Alex officially breaks up with Izzie, telling her that he loves her but deserves better . She leaves Seattle to start fresh . Several episodes later, Alex informs Meredith that Izzie sent divorce papers, which he signs in the episode "How Insensitive". In the sixth - season finale, Alex is shot and asks for Izzie . Imagining that Meredith's half - sister Lexie (Chyler Leigh) is Izzie, he apologizes and asks her never to leave him again . In the 300th episode, Alex reveals he never found out what happened to Izzie, but envisions a perfect, happy life for her, always smiling, now that he has moved on . </P> <P> Izzie was created by Grey's Anatomy producer Shonda Rhimes, with actress Katherine Heigl cast in the role . Heigl originally wanted to play Izzie as a brunette, but was requested to retain her natural blond for the part . Heigl's comprehension of medical procedures and terminology is slight; the actress explained that while she has an admiration for doctors, she is not as fascinated by medicine as other cast members . When Kate Walsh's character Addison Montgomery left Grey's Anatomy to launch the spin - off show Private Practice, Heigl disclosed that she had hoped for a spin - off for Izzie . </P> <P> Heigl declined to put her name forward for consideration at the 2008 Emmy Awards, claiming that she had been given insufficient material on the series to warrant a nomination . Following Heigl's statement, speculation arose that her character would suffer a brain tumor and be killed off Grey's Anatomy, substantiated by the announcement Jeffrey Dean Morgan would return to the series as Denny, who died at the end of season two . ABC's entertainment president Steve McPherson denied the rumor, stating: "There is an unbelievable storyline for her this year, which is really central to everything that's going to go on this season". </P> <P> Speculation resumed, however, when Dean Morgan returned to the show for a second time in its fifth season . Cast member James Pickens, Jr. announced that both Heigl and T.R. Knight were set to depart from the show, but he later retracted his comment . During the course of the fifth season, Izzie was diagnosed with metastatic melanoma (Stage IV) which spread to her liver, skin and brain . Following the show's one - hundredth episode wrap party, Heigl revealed she did not know if Izzie would survive, as no one on the production team would disclose her character's fate to her . It was confirmed in June 2009 that Heigl would return as Izzie for the show's sixth season . Heigl's appearances in the season were sporadic, seeing Izzie depart and return twice . Although she was scheduled to appear in the final five episodes of the season, Heigl requested that she be released from her contract 18 months early, and made her final appearance on January 21, 2010 . Heigl explained that she wanted to spend more time with her family, and did not think it would be respectful to Grey's Anatomy viewers to have Izzie return and depart yet again . Michael Ausiello spoke further on Katherine Heigl's perspective on Izzie's departure . He said, "(Katherine) thinks her Jan. 21 farewell - while not originally intended to be her last episode - oddly works as a bookend to Izzie's story . "Even though there's a part of me that would like to go back and do the quick Izzie farewell," she says, "I also think that my last scene - where Meredith says to Izzie,' Don't go, we're your family,' and Izzie's response was,' No you're not, you're just a bunch of people I worked with, and I can find that anywhere' - was kind of tragic and appropriate all at the same time . When I was playing the scene I was really trying to convey that, for Izzie, that was a lie that she had to tell herself to have the courage to have to move on ." </P>

When do izzie and alex get together again