Ellie (CHRISTINA RICCI) is a TV talk show producer who looks after her mildly geeky, comic-book-reading, high school-aged brother Jimmy (JEASSE EISNBERG) and remains patient with her commitment-phobic boyfriend Jake (JOSHUA JACKSON). One night Ellie and Jimmy's car hits a large animal on Mulholland Drive, such that they spin into a second car driven by Becky (SHANNON ELIZABETH).
When they attempt to pry her from her flipped-over car, the beast attacks, dragging Becky off to "tear her to shreds" (described but not shown) and leaving Ellie and Jimmy wounded. Some internet research and changes in behavior -- increased aggression and sexual appeal -- lead Jimmy to believe they are "cursed," that is, turning into werewolves.
While Jimmy tries to impress a pretty girl at school, Brooke (KRISTINA APANAU), her wrestler boyfriend Bo (MILO VENTIMIGLIA) calls him names (especially accusing him of being "gay"), then challenges him to wrestle in the gym. Jimmy's new strength allows him to win, and impress Brooke.
At the same time, Ellie is struggling with Jake's reputation as a womanizer and his seeming dedication to his work as a club designer (the latest job is "Tinsel," a Planet Hollywood-style joint that features monster movie memorabiliamemorabilia. The eventual and inevitable showdown with the werewolf takes place in this club on opening night, allowing for ironic backdrops (especially a wax figure of Lon Chaney's Wolfman in a life-size diorama), broken glass and mirrors, and screaming extras in fancy dress.