A few minutes before her wedding to Derek Dietl (Paul Rudd), a TV weatherman, Susan Murphy (Reese Witherspoon) is hit by a meteorite. The meteorite is infused with quantonium, a rare and powerful element that causes her to grow -- just as she begins to recite her vows -- to an enormous size. Targeted by the government as a monster, Susan is captured and imprisoned at a secret facility where other such oddities are being held, including Dr. Cockroach (Hugh Laurie), a mad scientist who accidentally transformed himself into a roach-human hybrid; B.O.B. (Seth Rogen), a gelatinous, brainless, but talkative mass brought to life in an experiment gone wrong; the Missing Link (Will Arnett), a Creature-from-the-Black-Lagoon-like lizard man; and the skyscraper-sized mutant larva Insectosaurus. Their jailer is General W.R. Monger (Kiefer Sutherland). When deranged alien overlord Gallaxhar (Rainn Wilson) comes to Earth to obtain the precious quantonium and conquer the world, U.S. President Hathaway (Stephen Colbert) offers the monsters their freedom in exchange for defeating the evil mastermind. They're turned loose in San Francisco and Gallaxhar's giant robot quickly fixates on Susan. It corners her on the Golden Gate Bridge. Thanks largely to Susan's amazing strength and determination to keep anyone from being hurt, the monsters are able to destroy the robot. Susan takes her monster friends to visit her parents, but they frighten all the neighbors at the backyard barbecue. Derek doesn't attend. When Susan seeks him out, he breaks up with her; it's apparent that all he cares about is his career, and he doesn't think a 50-foot wife will help him move into larger markets. Susan quickly realizes that she's better off without Derek, and that she likes her new self, her new abilities, and her new friends. She rejoins the other monsters only to be snatched up into Gallaxhar's spaceship. Insectosaurus is felled when it tries to help her. Despite Susan's brief escape and determined resistance, Gallaxhar extracts the quantonium from Susan's body and she returns to her original dimensions. The quantonium is key to Gallaxhar's evil plan to take over the world: it enables him to create legions of clones, who march around in formation saying "Hail Gallaxhar!" Meanwhile, the surviving monsters have snuck aboard to help Susan. They send the ship into self-destruct mode. Only Susan makes it out of the engine room before the doors close; Dr. Cockroach, B.O.B., and the Missing Link, stuck inside, insist that she escape without them. But Susan is made of tougher stuff than that; she goes back to Gallaxhar and tries to make him abort the self-destruct and release her friends. When Gallaxhar tries to escape, Susan regains possession of the quantonium and becomes a giant again. After she frees her friends, they're all rescued from the self-destructing ship by General Monger and Insectosaurus, who wasn't dead after all -- just busy metamorphosing into a moth the size of a 747. Before Susan and the monster squad are called away to save another day, there's a big celebration during which Derek tries to interview Susan. She spurns him and allows B.O.B. to swallow him and spit him out, a career-killing moment that Susan makes sure will be caught on camera.