George Simmons (Adam Sandler) is a very successful comedian and actor. However, he is self-absorbed, lonely and estranged from his family. When diagnosed with acute myeloid leukemia and informed that traditional treatments such as chemotherapy and radiation would be unlikely to benefit him, George is offered an experimental treatment which has an eight-percent chance of therapeutic response. This development causes him to descend into a depression and upon seeing old videos of his stand-up 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 at a supermarket delicatessen department, and who lives in an apartment with his two best friends, Mark Taylor Jackson (Jason Schwartzman), a moderately successful sitcom actor, and Leo Koenig (Jonah Hill), to whom George refers as “that triple-X-L version of you” (Leo later angrily learns that George was interested in employing Leo, in addition to Ira, but that Ira had intentionally and purposefully kept this from Leo). After an interesting conversation with Mark about Mark′s $25,000 weekly paychecks, a fellow stand-up comedienne, Daisy, (Aubrey Plaza), visits, and Mark magnanimously tells Ira that Mark will hold off having sex with Daisy for ten days in order for Ira to. Ira has an interesting conversation with an ex-convict fellow employee (RZA) about dental benefits and the unfortunate effect Ira′s comedy routine had on the ex-convict′s wife. George and Ira meet at a comedy club, where George takes the stage to deliver a dark routine. Ira is “up” next, and draws some laughs by mocking George′s morbidity (even though George is part of the audience). George calls Ira the next morning and asks him to write jokes for George's upcoming gig at a MySpace corporate event.

George Simmons (Adam Sandler) is a very successful comedian and actor. However, he is self-absorbed, lonely and estranged from his family. When diagnosed with acute myeloid leukemia and informed that traditional treatments such as chemotherapy and radiation would be unlikely to benefit him, George is offered an experimental treatment which has an eight-percent chance of therapeutic response. This development causes him to descend into a depression and upon seeing old videos of his stand-up 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 at a supermarket delicatessen department, and who lives in an apartment with his two best friends, Mark Taylor Jackson (Jason Schwartzman), a moderately successful sitcom actor, and Leo Koenig (Jonah Hill), to whom George refers as “that triple-X-L version of you” (Leo later angrily learns that George was interested in employing Leo, in addition to Ira, but that Ira had intentionally and purposefully kept this from Leo). After an interesting conversation with Mark about Mark′s $25,000 weekly paychecks, a fellow stand-up comedienne, Daisy, (Aubrey Plaza), visits, and Mark magnanimously tells Ira that Mark will hold off having sex with Daisy for ten days in order for Ira to. Ira has an interesting conversation with an ex-convict fellow employee (RZA) about dental benefits and the unfortunate effect Ira′s comedy routine had on the ex-convict′s wife. George and Ira meet at a comedy club, where George takes the stage to deliver a dark routine. Ira is “up” next, and draws some laughs by mocking George′s morbidity (even though George is part of the audience). George calls Ira the next morning and asks him to write jokes for George's upcoming gig at a MySpace corporate event.

The event goes well and George hires Ira as his “assistant.” George mentors Ira with regard to some perhaps funny but ultimately self-defeating aspects of Ira′s comedy routine, involving certain bodily functions—Ira′s fascination with which, George comments, is sure to have a chilling effect on Ira′s romantic and sexual potential. Informed of his condition, Ira cares for George through the treatment. After an interesting walking conversation between Ira, Mark, and Leo, in which Ira and Leo declare that there is compelling evidence that Mark′s deceased grandfather is “in hell playing backgammon with Hitler,” eventually, Ira implores George to tell people about his disease. George does call his ex-girlfriend, Laura, to apologize for his continual infidelities when they were together, but does not tell her why he is having a change of heart. Meanwhile, at Mark’s, Ira′s and Leo′s home, Ira sees Daisy come out of Mark′s bedroom. Ira decides that, even after Ira had asked Daisy to a Wilco concert, that Daisy has had sex with Mark. Ira confronts Daisy, in what Daisy observes to be their lengthiest conversation to that point in time, about having had sex with Mark while in the planning stages of attending the concert together. Meanwhile, Leo arrives, and comments, on seeing Mark and Daisy standing next to one another, declaring that Leo is himself “getting” a “vibe,” and has therefore developed a “quarter-chub.” Laura comes to one of George′s shows. She later tells George that her husband, Clarke, cheats on her as well when he travels to China on business. She regrets leaving George, and they end up becoming reconciled.

George′s physician (a Scandinavian George and Ira previously mocked for the physician′s ethnicity in common with actors who appeared in the movies Die Hard and The Matrix Reloaded, and for his common ethnicity with the founder of IKEA) tells him that the medicine has worked: George, almost miraculously, has no traces of the disease, but that it could resurface. Ira is happy; however, 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 free of disease. George later explains that he didn′t want to jinx it. They embrace and she invites George and Ira to her house in Marin County.

George and Ira spend time with Laura and her daughters. George and Laura sneak into the guest house together, and indulge in some extramarital sexual activities. Ira tells both daughters that George is healthy now. Clarke (Eric Bana) unexpectedly arrives home; Laura asks George and Ira to maintain the façade of George being deathly sick. In the morning, Clarke bids 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 free of disease and “calls Clarke out” on his infidelity; he drives off. Laura decides to leave him. Ira thinks George should leave because it is not worth it to ruin a 12-year marriage, but George threatens to fire him.

The next day, George, Ira, and Laura watch video of Laura′s daughter, Mabel, performing the song “Memory” from Cats. Ira and Laura find the performance moving, but George inadvertently mocks it. 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 a mere flirtation. Ira, having followed Laura and Clarke to the Taiwanese Great China Airlines First class lounge, gets caught by Clarke trying to sneak away (Ira protests that he was merely looking for “Panda Express”). Laura is then forced to tell Clarke she slept with George.

Clarke chases George out of his house, throwing his fists at him. George asks Laura to explain; however, Laura “sides” with Clarke. Heading back to Los Angeles, George berates Ira for his betrayal and terminates his employment. Ira upbraids George for not learning anything from his experience, saying that his insensitivity hasn′t changed. Ira returns to his old job at the deli department. George attends Ira′s stand-up and watches him being 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.

Dave Attell, Sarah Silverman, Norm MacDonald, Paul Reiser, Tom Anderson, Charles Fleischer, George Wallace, and Andy Dick made cameo appearances as themselves in the roles of George's fellow comedians. Rapper Eminem, comedian Ray Romano, musician James Taylor, MADtv member Nicole Parker, and newcomer Bo Burnham also appeared in small roles. Undeclared alum Carla Gallo had a cameo in the film as a character on Yo Teach!, the television show within the film that Mark stars in, while Justin Long and Apatow regular Ken Jeong have cameos in the film as characters in movies for which George is famous. Owen Wilson and Elizabeth Banks are featured on posters for fake movies in which George starred.. Bryan Batt makes an appearance as George's agent. Musicians Jon Brion, Sebastian Steinberg, and James Gadson appear in the film as members of George's jam band. Comedians Rod Man, Budd Friedman, Monty Hoffman, Mark Schiff, Orny Adams, Al Lubel, and Jerry Minor appear as themselves. Comedienne/producer/writer Carol Leifer appears as herself. Peter Boffemmyer appears briefly as a man sitting in the doctor's office.

Judd Apatow had expressed his desire to make a stand-up comedian mentor film loosely based on his own early experiences as a struggling performer. He could not come up with an interesting idea since most of his mentors were kind to him. He then thought of making a film about a mentor facing a life crisis, and decided to have his former roommate Adam Sandler play that role. They discussed making the film almost two years prior to production.

Apatow had cast Sandler, Seth Rogen, and Leslie Mann as the three leads in March 2008. Eric Bana, Jonah Hill, and Jason Schwartzman were cast in June 2008 when the title of the film was announced. When asked about the decision to cast Bana, Apatow said that both he and Rogen are fans of his films as well as his sketch comedy work in his native Australia. Rogen additionally commented they cast him as the husband because he was someone who would be considered an intimidating presence to both Sandler and Rogen. Bana mentioned that he decided to make his character an Australian so he could improvise more.