Bob (MATT DAMON) and Walt Tenor (GREG KINNEAR) are conjoined twins who've grown up on Martha's Vineyard doing everything together. While Walt is an aspiring actor, Bob is content with running their burger joint and dreaming of his California Internet girlfriend who he's known for years but has never met.
Despite the shared liver and nine inches of flesh on their sides that keep them together, the two have long agreed not to old each other back, and surgery is out of the question since it could be dangerous to Walt. Thus, Bob agrees to move to Hollywood with Walt so that he can try to make it in the movies.
After repeated rejections, they run into lingerie model and aspiring actress April Mercedes (EVA MENDES) who introduces the two to her agent, Morty O'Reilly (SEYMOUR CASSEL), who takes on Walt as his client.
The first job he finds for Walt is a bust, but he and Bob accidentally run into Cher (CHER) who isn't happy with her new TV show. With final say on who's cast as her co-star, she chooses Walt knowing full well that the network will cancel the show when they learn about his condition.
They don't, however, and the show becomes a surprise hit, propelling Walt into stardom. Bob, however, feels like little more than a gimmick, a point he tries to keep secret from May Fong (WEN YANN SHIH), his Internet girlfriend who lives nearby.
With their physical condition increasingly getting in their way, Bob and Walt must decide whether to go on living as they always have or take the physical and emotional risk of being surgically separated.