Tom (STEVE MARTIN) and Kate Baker (BONNIE HUNT) live in the small town of Midland where Tom is the successful Division III college football coach and Kate is trying her hand at writing a book. When they're not doing that, they're trying to raise their twelve kids as best they can. The oldest, Nora (PIPER PERABO) has already moved out and in with Hank (ASHTON KUTCHER) a self-absorbed TV commercial actor boyfriend.
The next oldest, Charlie (TOM WELLING) and Lorraine (HILARY DUFF), are high schoolers who aren't particularly enamored with living with the rest of their siblings. They include Jake (JACOB SMITH), Sarah (ALYSON STONER), Kevin (KEVIN G. SCHMIDT), Kim (MORGAN YORK), Jessica (LILIANA MUMY), Mike (BLAKE WOODRUFF) and twins Nigel and Kyle (BRENT & SHANE KINSMAN). Then there's Mark (FORREST LANDIS), the one Baker who's so unlike the others that his siblings call him "Fedex" since they claim he was delivered rather than born into their family.
When Tom's friend Shake Maguire (RICHARD JENKINS) offers him the prestigious job of coaching at their old college, he and Kate realize he can't pass on the opportunity. Accordingly, the kids reluctantly pack up their belongings and move to a new home in a new city.
With Kate's new book suddenly taking off and Tom being so busy with coaching, the family unity begins to suffer. From that point on, the parents must decide how to balance their professional and family responsibilities.