When California resident Susan Murphy (Reese Witherspoon) mysteriously grows to 49 ft 11 in, she is labelled a monster and captured by the military. She is remanded to an institution that houses other monsters: Dr. Cockroach, Ph.D., an insect-headed mad scientist (Hugh Laurie), the Missing Link, a thousands-of-years-old fish-man (Will Arnett), B.O.B., a gelatin-like, jolly, indestructible monster (Seth Rogen) and Insectosaurus (Jimmy Kimmel), a fuzzy bug that stands at 350 feet tall, making even Susan look tiny by comparison. When a UFO lands and an alien overlord named Gallaxhar (Rainn Wilson) demands that Earth be given to them, General W.R. Monger (Kiefer Sutherland) suggests to the President (Stephen Colbert) that the monsters can provide the firepower to defeat the aliens.


Monsters/Aliens

* Reese Witherspoon as Susan Murphy (Ginormica): On the day she was supposed to marry local weatherman Derek Dietl, she was hit by a meteor filled with a strange substance that mutated her DNA, causing her to grow into a 49 foot 11 inch tall woman. She is impervious to nuclear and atomic forces. She is based on the film Attack of the 50 Foot Woman. She has a huge heart, (emotionally.) She seems to be good friends with B.O.B, Missing link and insectosaurus.


* Hugh Laurie as Dr. Cockroach, Ph.D.: When his teleportation device backfired, he ended up with the head of a cockroach. He is a great inventor and a mechanical genius. He seems to prefer being referred to as a mad scientist. He is most likely based on the film The Fly. He has a amazingly low temper and preforms expirements on the other monsters in order to make them stronger.

* Will Arnett as The Missing Link: A 20,000 year old frozen fish-ape hybrid thawed out by scientists two thousand years after the Ice Age, he is a bit out of shape and is shown saying "Paps a bit out of shape". He and Insectosaurus seem to be good friends, suggested by the fact that he can understand what he's saying, tells people not to scare him and says that he wont let "the humans" hurt him. Based on the Creature from the Black Lagoon.

* Seth Rogen as Bicarbonate Ostylezene Benzoate" ("B.O.B."): Created by the accidental mixture of a genetically altered tomato and a chemically-altered ranch-flavored dessert topping. He is an indestructible gelatinous mass with no brain ("It turns out you don't need one!"). It is based on The Blob, although the genetically engineering tomatoes could be a likely reference to Attack of the Killer Tomatoes. He is slow witted and has a dangerously large appetite, eating almost anything,(except humans and monsters.)


* Jimmy Kimmel as Insectosaurus: Transformed by nuclear radiation from a one inch grub into a 350 foot monster. He has the ability to shoot silk from his nostrils, and speaks in unusual roars which only The Missing Link can understand. He is a crossbread bettween a beetle, grub, silkworm and, possibly ,a guinea pig. It seems it is actually very emotionally sensitive and is extremely friendly, only eating buildings as a sign of hunger. Seems to be based on many of the Japanese-styled monsters.


* Rainn Wilson as Gallaxhar: An alien leader who plans to take over the planet Earth.

Humans

* Stephen Colbert as President Hathaway: President of the United States who does not want to go down into history as the president in office when the world came to an end, and therefore agrees with General Monger's plan to defeat the aliens.


* Kiefer Sutherland as General W.R. Monger: Comes up with a plan to let the imprisoned monsters fight the aliens. He is possibly a reference to the Brigadier General Jack D. Ripper from Dr. Strangelove

* Paul Rudd as Derek Dietl: Susan Murphy's fiancé.