George Simmons (Adam Sandler) is an extremely successful comedian and actor. But he is very self-absorbed, lonely and estranged from his family by choice. He is subsequently diagnosed with acute myeloid leukemia and is informed that traditional treatments such as chemotherapy and radiation would be unlikely to benefit him, so he embarks on an experimental treatment with an 8% chance of response. Consequently, he falls into a depression and upon seeing old tapes of his standup days, he decides to return to his roots and do stand-up comedy.

Ira Wright (Seth Rogen) is an aspiring stand-up comedian who dreams of quitting his day job. George and Ira meet at a comedy club, where George unexpectedly takes the stage to deliver a dark routine. Ira is forced to follow and draws some laughs by mocking George's morbidity as he watches from the back. George calls Ira the next morning asking him to write jokes for him to perform at a MySpace corporate event.

The event goes well and George hires Ira as an assistant. George informs Ira of his condition and Ira cares for George through the treatment. Eventually, Ira breaks down, begging George to tell people about his prognosis. While in the process of telling his friends, George is visited by his ex-girlfriend, Laura (Leslie Mann) who he excessively cheated on. Laura says that her Husband Clarke is cheating on her as well while he's away on business. She regrets leaving George and they reconcile.

George sees his doctor and learns that the medicine has worked; he has no traces of the disease, but it could resurface. Ira is happy but George is unsure what to do with his life. He decides he wants a long-term relationship and calls Laura, but does not tell her the news. George and Ira go to San Francisco to perform; Laura meets them there. George makes Ira tell Laura during intermission that he is better. George later explains that he didn't want to jinx it. They embrace and she invites George and Ira to her house in Northern California.

George and Ira spend time with his and her daughters. George and Laura sneak into the guest house, and George performs cunnilingus on her. Ira tells both daughters that George is healthy now. Clarke unexpectedly arrives home; Laura asks George and Ira to keep up the faзade of George still being sick.

In the morning, Clarke gives George a tearful goodbye. His daughters reveal that George is actually healthy. Clarke confronts Laura and suspects she is cheating. Laura tries to explain that George may not be entirely better and calls Clarke out on his infidelity so Clarke drives off. Laura decides to leave him. Ira thinks George should leave because it is not worth it to ruin a twelve-year marriage, but George threatens to fire him.

The next day, George, Ira, and Laura watch video of her daughter Mabel performing "Memory" from Cats. Ira and Laura find the performance moving, but George thinks it's hilarious and offends Laura. Laura leaves for the airport to tell Clarke she is leaving him. Ira lies to George and follows her. Clarke tells Laura that he wants to give their marriage another try and that he only cheated on her twice. Laura agrees and says her fling with George was just a flirtation. Ira gets caught by Clarke trying to sneak away. Laura is forced to tell Clarke she slept with George.

Clarke chases George out of his house, throwing fists at him. George asks Laura to explain but she sides with her husband. Heading back to Los Angeles, George berates Ira for his betrayal and fires him. Ira fires back at George for not learning from his experience and that his insensitivity hasn't changed.

Ira goes back to his old job. George attends Ira's stand-up and watches him being much more confident on stage. The next day, George finds Ira at work and admits that even though he is no longer sick, his attitude needs improvement. George offers Ira jokes he wrote down, proving he is making an attempt to become a better person.