Here, Zsuzsa Fabry and colleagues address the question of whether the unique cellular environment of the central nervous system (CNS) contributes to the observed differences in immunological functions between the CNS and other organs. In particular, they discuss the significance within the CNS of the blood-brain barrier, the nonconstitutive expression of major histocompatibility complex (MHC) molecules, the unusual set of potential antigen-presenting and effector cells, and the production of immune or neuromediators from various cellular sources.