Complement is an important component of both the innate and adaptive immune response that contributes to host defense in a variety of mechanisms, including inflammation, phagocytosis and cell lysis. Complement proteins are produced by all cell types in the CNS, and the same effector functions that protect the host from pathogens can mediate inflammation and tissue destruction in CNS diseases, leading to neurological deficits or even death. In the last 10 years, the development of complement inhibitors and a variety of animal models for CNS diseases has revealed that targeted inhibition of complement offers significant therapeutic potential. This review discusses the subtleties of targeted complement inhibition in CNS disease as an emerging therapeutic strategy.