The precise role of T cells in multiple sclerosis (MS) remains to be defined. No MS-specific antigen has been found. The autoimmune hypothesis for MS rests on immune changes seen in the spinal fluid and brain and on the demonstration, in an experimental animal model, that T cells raised to myelin basic protein transfer demyelination. In this review, Virginia Calder and colleagues focus on recent studies suggesting that in MS, the initial T-cell response occurs within the central nervous system and that the blood poorly reflects this immune activity. This contrasts with the animal model, experimental allergic encephalomyelitis, where the initial immune response is peripheral.