ECHO (Dushku) is an "Active," a member of a highly illegal and underground group of individuals who have had their personalities wiped clean so they can be imprinted with any number of new personas. Hired by the wealthy, powerful and connected, the Actives don’t just perform their hired roles, they wholly become – with mind, personality and physiology – whomever the client wants or needs them to be. Whether imprinted to be a lover, an assassin, a corporate negotiator or a best friend, the Actives know no other life than the specific engagements they are in at that time.
Confined between missions to a secret facility known as the "Dollhouse," Echo and the other Actives including SIERRA (Dichen Lachman) and VICTOR (Enver Gjokaj) are assigned engagements by ADELLE (Olivia Williams), one of the Dollhouse leaders. After each scenario, Echo, always under the watchful eye of her handler BOYD (Harry Lennix), returns to the mysterious Dollhouse where her thoughts, feelings, experiences and knowledge are erased by TOPHER (Fran Kranz), the Dollhouse’s genius programmer.
Echo enters the next scenario with no memory of before. Or does she?
As the series progresses, FBI Agent PAUL BALLARD (Tahmoh Penikett) pieces together clues that lead him closer to the Dollhouse, while Echo stops forgetting, her memories begin to return and she slowly pieces together her mysterious past.