While performing on Lake Springfield, rock band Green Day are killed when the pollution in the lake erodes their barge. At a memorial service, Grampa has a prophetic vision in which he predicts the impending doom of the town, but only Marge takes it seriously. Lisa and an Irish boy named Colin, with whom she has fallen in love, hold a meeting where they convince the town to clean up the lake.
Meanwhile, Homer adopts a pig from the Krusty Burger. Homer stores the pig's feces in an overflowing silo which Marge tells him to dispose of safely. However, Homer gets distracted and instead dumps the silo in the lake, re-polluting it. Moments later, a squirrel jumps into the lake and becomes severely mutated. Nearby, Flanders and Bart discover the squirrel during a hike, and the EPA captures it. Russ Cargill, head of the EPA, presents five options to President Schwarzenegger, who randomly picks the action of enclosing Springfield in a giant glass dome. When the police discover Homer's silo in the lake, an angry mob of townspeople approach the Simpsons' home and sets it on fire, but the family escapes through a sinkhole and flees to Alaska.
Cracks start to appear in the dome and Cargill, not wanting news of what he has done to become widespread, plans to destroy Springfield. In Alaska, the Simpsons see an advertisement for a new Grand Canyon to be located on the site that was Springfield. Marge and the kids decide to go and save the town, but Homer refuses to help the people who tried to kill them. The family abandons Homer and leaves but are captured by the EPA and placed back in the dome. After a visit from a mysterious Inuit shaman, Homer has an epiphany and believes he must save the town in order to save himself.
As he arrives at Springfield to do so, a helicopter lowers a bomb suspended by rope through a hole in the dome. Homer climbs to the peak of the dome and descends the rope, knocking the escaping townspeople and bomb off. Homer grabs the bomb and a motorcycle. After reuniting with Bart, they cycle up the side of the dome and Bart tosses the bomb through the hole, seconds before detonation. The bomb explodes, shattering the dome. The town praises Homer, who rides off with Marge on the motorcycle into the sunset. The townspeople begin restoring Springfield back to normal.
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