Five years prior to the series, a massive explosion released high concentrations of nanites into the atmosphere, infecting almost every living thing on Earth. These nanites may randomly activate inside their hosts, mutating the subject into a monster known as an E.V.O. (short for “Exponentially Variegated Organism”). Though some E.V.O.s retain human-level sanity, intelligence, and memory and are in full control of their special E.V.O. abilities, most go violently berserk and cause widespread chaos and destruction. An international organization known as Providence exists to combat the E.V.O. threat.

Rex is a fifteen-year-old (sixteen, later on in the series) amnesiac teenager who is an E.V.O. Unlike most E.V.O.s, he lacks any physical deformation but forgets about his past. He is also able to control his active nanites, allowing him to manifest a wide variety of various bio-mechanical abilities and powers. However, Rex is truly unique because he has the ability to deactivate nanites inside other E.V.O.s, effectively curing them of their monstrous mutations. Working for Providence under Agent Six, Rex uses his unique abilities to stop and cure rampant E.V.O.s. His archenemy is Van Kleiss, an E.V.O. scientist who hates and despises Providence. He believes nanite mutations are a gift and should be utilized accordingly. Van Kleiss is connected not only to the original Event which released the nanites upon the Earth, but to Rex himself. Though it was never stated Rex may have the ability to turn himself into the mechanical E.V.O. in the episode “Promises, Promises” in season one, this was shown to be theoretically possible when Rex started combining his E.V.O. powers so if he were to combine them all it could make him into the giant bio-mechanical E.V.O. previously seen and mentioned.