Upset when his wife leaves him, Lazarus (SAMUEL L. JACKSON) starts to drink heavily and literally sing the blues. But his sense of abandonment is nothing compared to Rae's (CHRISTINA RICCI), who is devastated when her National Guardsman boyfriend Ronnie (JUSTIN TIMBERLAKE) leaves for training, en route to Iraq. Though he says he's enlisted in order to secure their future, she fears he'll never come back.
Worse, Rae suffers from a severe form of nymphomania, because (shadowy flashbacks insinuate) she was abused as a child. Now, when Rae is upset, she begins to shudder and moan, then seeks out the nearest man in order to have sex. While she has a regular tryst set up with Tehronne (DAVID BANNER), she runs into trouble when she meets a group of young men at a bar and drinks herself into oblivion. After they have sex with her on a football field, she gets a ride home from Ronnie's best friend Gill (MICHAEL RAYMOND JAMES), who beats her unconscious and leaves her on the road to die.
This is where Lazarus' and Rae's paths cross. He finds her the next morning at the end of his driveway, takes her inside, and decides to "cure" her. As she's unable to control her sexual urges, he reasons, her range of motion must be limited. And so Lazarus chains her to his radiator. Their time together -- several days -- involves fierce arguments, Rae's attempted escapes, some medicine (Lazarus gets a syrup from the local pharmacy, and flirts with Angela [S. EPATHA MERKERSON]), and Lazarus' singing. One night he takes her to a blues club where he performs and she drinks and dances very lewdly. Still, she's among people who mean her no harm, and so she comes to trust Lazarus, even to love him as a kind of father figure.
Ronnie comes home early, when the military discharges him (he has his own illness, meaning that he has panic attacks). Upon hearing that Rae has been abused and then, that she's living with a black man, he charges off in search of vengeance, against Gill and Lazarus.