On her wedding day, Susan Murphy (Reese Witherspoon) is hit by a meteorite infused with Quantonium, a rare and powerful element that causes her to grow 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 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 larvae Insectosaurus. When deranged alien overlord Gallaxhar (Rainn Wilson) arrives on Earth to obtain the precious Quantonium and conquer the world, President Hathaway (Stephen Colbert) offers the monsters their freedom in exchange for defeating the evil mastermind and his legion of robots and clones.