Forty years prior to the events of the series, disaster struck. The world was turned into a vast desert wasteland and the survivors were left without memories. The story takes place in Paradigm City, a corporate police state run by the Paradigm Corporation. The town is recognized for its geodesic domes, giant structures that house the richer citizens and segregate the poor.
The Big O deals with the nature of memories. A memory is a record stored in the brain of an organism, but in Paradigm City memories can mean much more. "Memories" (メモリー, Memorī?) embody the lost knowledge of its residents, and can take the form of records from before the Event, forgotten artifacts from the previous era or manifest themselves as recollection, hallucinations and recurring dreams.
Roger Smith is the series protagonist. As a Negotiator, his job entails finding a resolution for the troubles of the City of Amnesia. He'd negotiate almost anything for anyone, but he is a professional and expects the parties involved to behave professionally. When memories betray the people and force them to reawaken monstrosities of the city's past, Roger's only option is to fight back with a monstrosity of his own, the black megadeus Big O.