Rose (TONI COLLETTE) and Maggie Feller (CAMERON DIAZ) are sisters who couldn't be more different if they were strangers. Rose is a successful if frumpy and slightly overweight lawyer who's shocked when she manages to bed her boss, Jim Danvers (RICHARD BURGI), since she doesn't otherwise have much luck with men. Maggie, on the other hand, is an unemployed partygoer who has no problem having casual sex, such as with a former classmate at a high school reunion.
Her partying ways, however, eventually are too much for her step-mom Sydelle (CANDICE AZZARA) who kicks her out of her and husband Michael's (KEN HOWARD) house. With nowhere else to go, Maggie moves in with Rose, but her lifestyle, not to mention her seducing Jim while Rose is away, eventually drives a wedge between them, with Rose ordering Maggie out.
Desperate for a new start, Maggie heads south for a surprise visit to her widowed grandmother, Ella Hirsch (SHIRLEY MacLAINE), who hasn't seen the sisters since they were girls due to circumstances beyond her control. Ella is surprised but happy about the visit, and manages to convince Maggie to get a job in a nearby nursing home, all while Maggie tries to convince her grandma to get to know widower Lewis Feldman (JERRY ADLER) who's obviously sweet on her.
Rose, meanwhile, has left the legal world and started her own pet walking service, all while getting to know former coworker Simon Stein (MARK FEUERSTEIN) who's as passionate about her as he is the rest of his life. With the sisters in opposite parts of the country, they rediscover themselves and learn things about each other, their grandmother and the past tragic situation that changed their lives forever.