Susan Murphy (Reese Witherspoon) is about to be married to Derek the tv weatherman when she is struck by a meteorite and starts to transform into a giant 50ft woman. Taken to a secret government lair for testing, she meets up with her fellow monsters - BOB a gelatinous mass, Dr. Cockroach PhD, the Missing Link and Insectasaurus (a giant bug), who have been kept prisoner for 50 years. When a giant alien robot lands on earth causing destruction, the President calls for the only weapon they can use to fight back - the Monsters!

When they save the world from the evil robot sent by Gallaxhar, they are allowed a bit of freedom and go to Susan's parents - but they just feel more lost and Susan is dumped by Derek.
  Sitting on a petrol station roof, Susan is beamed up to the alien spaceship where she meets Gallaxhar and he demands the precious quantonium back from her body. Insectasaurus is hit by a blast from the ship and is downed, seemingly dead. 
  Susan breaks free from the electric cage and is too strong for Gallaxhar as she smashes her way through the ship, but is caught in a trap and the metal is sucked out of her body, sending her back to her normal height.
  The Monsters, led by the army guy, attack the ship and manage to get on board. Meanwhile Gallaxhar creates thousands of clones to take over the earth, but the monsters manage to blend in and take out the central system causing a self-destruct sequence to start.
  Trying to escape, only Susan makes it out and the monsters tell her to get away and save herself.  She confronts Gallaxhar and covers herself with the quantonium again, growing to her giant size with super strength.  She rescues her pals but they are still trapped on the hovering ship ... until the army captain shows up riding on a flying Insectasaurus who has turned into a butterfly.

They fly away to safety, as the alien spaceship explodes.

They are now heroes again, and Derek wants to be back in Susan's life - in return for an interview so he can secure a better job in New York.    He is thrown up in the air and swallowed by BOB, live on air.  The monsters are then told about a radioactive snail attacking Paris, and are off again to save the day.