In the town of Springfield where the nuclear power plant run by Montgomery Burns (voice of HARRY SHEARER) and his loyal assistant Smithers (voice of HARRY SHEARER) is the biggest player around, reactor worker Homer Simpson (voice of DAN CASTELLANETA) might be the biggest buffoon. Self-centered and fun-loving, his impulsive ways usually lead to some degree of disaster that he and/or others must mitigate. Among those who usually help him are his stay-at-home wife, Marge (voice of JULIE KAVNER), who holds down the fort while trying to make sure their oldest child, the mischievous Bart (voice of NANCY CARTWRIGHT), stays out of trouble.
She doesn't have the same worries about his younger sister, Lisa (voice of YEARDLEY SMITH), a smart and sensitive girl who's obsessed with helping the environment, a point she shares with Irish newcomer Colin (voice of TRESS MacNEILLE). Toddler Maggie is too young to cause too many headaches, which usually also holds true for Homer's dad, Grampa (voice of DAN CASTELLANETA), although he's recently had a religious experience at church that has Marge trying to decipher his mysterious mutterings.
Little do they know that it has to do with the coming of environmental disaster in their town, caused, as to be expected, by Homer. In a hurry to dispose of pig and human waste, he breaks the law by dumping it into the local lake, thus creating a mutant creature that immediately draws the attention of EPA head honcho, Russ Cargill (voice of ALBERT BROOKS).
He convinces President Arnold Schwarzenegger (voice of HARRY SHEARER) that they must do something, and that turns out to be covering Springfield in a huge, transparent dome. That worries the likes of the ever-optimistic Ned Flanders (voice of HARRY SHEARER) who lives next door, but only serves to irritate barkeep Moe (voice of HANK AZARIA) and others who eventually turn on Homer, thus forcing the family to flee.
With the lives of those still stuck in Springfield -- including Bart's friend Milhouse (voice of PAMELA HAYDEN), Chief of Police Wiggum (voice of HANK AZARIA), local hick Cletus (voice of HANK AZARIA), town drunk Barney (voice of DAN CASTELLANETA), TV personality Krusty the Clown (voice of DAN CASTELLANETA) and many others -- at stake, Homer and his family must decide what to do to help.