After Homer accidentally pollutes the town's water supply, Springfield is encased in a gigantic dome by the EPA and the Simpsons are declared fugitives.
'Toon star Roger is worried that his wife Jessica is playing pattycake with someone else, so the studio hires detective Eddie Valiant to snoop on her. But the stakes are quickly raised when Marvin Acme is found dead and Roger is the prime suspect.
A bizarre accident lands Frank Harris in Cool World, a realm of cartoons. Years later, cartoonist Jack Deebs, who's been drawing Cool World, crosses over as well. He sets his lustful sights on animated femme fatale Holli Would, but she's got plans of her own to become real, and it's up to Frank to stop her.
