Eliot Arnold (TIM ALLEN) once had a good life, as he was happily married and an 18-year employee with the Miami Herald writing humor columns. After being fired and cheated on, however, Eliot has decided to reinvent himself with his own ad agency. He isn't happy, however, especially when dealing with obnoxious clients such as Bruce (MICHEAL McSHANE), a beer man, and knowing that his teenage son, Matt (BEN FOSTER), considers him to be a "loser."
Matt and his friend Andrew (DJ QUALLS) are interested in making a water gun hit on droll classmate Jenny Herk (ZOOEY DESCHANEL). She lives with her mom, Anna (RENE RUSSO), and stepfather Arthur (STANLEY TUCCI), although neither of them can stand him. The same holds true for his company that's decided to hire two hitmen from Newark, Henry (DENNIS FARINA) and his dimwitted partner, Leonard (JACK KEHLER), to kill Arthur for stealing money from them.
Meanwhile, the Herks' immigrant housekeeper, Nina (SOFIA VERGARA), has fallen for a Frito-loving drifter by the name of Puggy (JASON LEE) who recently had a run-in with two moronic lowlifes, Snake Dupree (TOM SIZEMORE) and Eddie Ledbetter (JOHNNY KNOXVILLE), in a bar serving as a cover for two Russian arms dealers.
The simultaneous hit attempts on Jenny and Arthur eventually result in the arrival of Miami police officers Monica Romero (JANEANE GAROFALO) and Walter Kramitz (PATRICK WARBURTON), who later must deal with twins Jack & Ralph Pendick (ANDY RICHTER), two overzealous security guards.
Things become more complicated when the Russian arms dealers sell a nuclear suitcase bomb to Arthur that's then stolen by Snake and Eddie who are unaware of what it really is. FBI Agents Greer (DWIGHT "HEAVY D" MYERS) and Seitz (OMAR EPPS) then arrive on the scene, resulting in a wild chase that eventually involves everyone else and leads to the airport as the lowlifes attempt to flee the country.