The show follows an organization that employs mind-wiped DNA-altered humans known as Dolls who are implanted with false memories and skills for various missions and tasks. When they are not 'at work' they are living in a real life Dollhouse which gives the show the name. One of those mind-wiped humans, a young woman named Echo, is slowly starting to become aware of herself and what's going on - all the while somebody on the outside is trying to bring the Dollhouse  down while getting closer to Echo - possibly not aware that she is one of the Dolls he is after.