George Simmons (Adam Sandler) is a very successful 40-something comedian and actor. However, he is self-absorbed, lonely, and estranged from his family. When diagnosed with acute Myeloid leukemia, George is offered an experimental treatment that has an eight-percent chance of therapeutic response. Believing he is about to die; he decides to return to his roots and do stand-up comedy. Ira Wright (Seth Rogen) is an aspiring stand-up comedian who lives in an apartment with his two best friends in Los Angeles, Mark Taylor Jackson and Leo Koenig (Jason Schwartzman and Jonah Hill).Mark stars in a sitcom, Yo Teach, where he plays a teacher for a group of misfit students. Despite the obvious failings of the show, Mark constantly brags about his high income. When fellow stand-up comedienne Daisy (Aubrey Plaza) visits the apartment, Mark magnanimously tells Ira that he will hold off having sex with her for ten days in order for Ira to make a play for her. At a comedy club, George takes the stage to deliver a dark routine, which Ira mocks in his follow-on act. George calls Ira the next morning and asks him to write jokes for George's upcoming gig at a MySpace corporate event.George hires Ira as his assistant. When George tells him about his condition, Ira cares for him through the treatment. Ira implores George to tell people about his disease. George previously had called his ex-fiance, Laura (Leslie Mann), to apologize for his infidelities when they were together, but does not tell her why he is having a change of heart. Meanwhile, Ira awkwardly asks Daisy out, but later discovers that she and Mark have slept together, and angrily cuts off all ties with her.Laura learns about George's illness, visits him at his house, and confesses that her husband, Clarke, cheats on her as well. They reconcile and tentatively become friends. George's physician tells him that the leukemia is in remission. George is happy but is unsure what to do with his life now. He decides he wants a long-term relationship and calls Laura but does not tell her the news. George and Ira go to a gig in San Francisco; Laura meets them there. George makes Ira tell Laura during intermission that he is free of disease. George later explains that he did not want to jinx it.Laura invites George and Ira to her house in Marin County. George and Ira spend time with Laura and her two young daughters. George and Laura sneak into the guest house together to have sex; meanwhile, Ira tells both daughters that George is healthy. When Clarke (Eric Bana) unexpectedly arrives, Laura asks George to maintain the facade of being terminally ill. In the morning, Clarke bids George a tearful goodbye - which is cut short when his daughters reveal that George is actually healthy now. Clarke confronts Laura and accuses her of cheating.In response, Laura confronts him with his infidelity, and he drives off in a huff. Laura tells George that she plans to leave Clarke; George is overjoyed, but Ira tells him their affair will destroy a family. Angered, George threatens to fire him. The next day, George, Ira, and Laura watch the video of Laura's oldest daughter, Mabel, performing the song "Memory" from the musical Cats; Ira and Laura find the performance moving, but George appears bored. Laura leaves for the airport to tell Clarke she is leaving him; Ira lies to George and follows her.At the airport, Clarke confesses his infidelity to Laura, and pleads with her to give their marriage another try. Laura agrees and says her affair with George was a mere flirtation. They discover Ira following them and goad him into admitting that he is trying to stop George and Laura from running off together. An enraged Clarke chases George out of his house and beats him up. George demands Laura choose between him and Clarke; she chooses her husband, and bids George a tearful goodbye.Heading back to Los Angeles, George berates Ira for his betrayal and fires him. Ira upbraids George for not learning anything from his near-death experience and tells him that he will never be able to escape his own personal failings because of his selfish nature. Ira returns to his old job at the deli department while he starts to date Daisy. George attends Ira's stand-up act and sees that his old assistant has become a far more confident performer. The next day, George finds Ira at work and admits that even though he is no longer sick, his attitude needs improvement. The film ends with George and Ira telling each other jokes as they laugh together and repair their friendship.
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