Multiple sclerosis (MS) is an inflammatory disease which exclusively affects the white matter of the central nervous system (CNS). Although there is a localized immune response within the CNS, immune abnormalities that correlate with disease activity are also found in the peripheral immune compartment of MS patients. These abnormalities primarily involve immunoregulatory defects in T-cell function that are associated with T- and B-cell hyperactivity. In this review, David Hafler and Howard Weiner discuss the evidence that there are T-cell abnormalities in MS similar to those observed in other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, and that the immunoregulatory defects in the blood of MS patients appear to be accompanied by the rapid migration of activated T cells from the peripheral blood to the CNS. That immunotherapy directed at the peripheral immune compartment affects the disease process supports their argument. Specifically, total lymphoid irradiation of the peripheral immune compartment ameliorates progressive MS whereas systemic treatment with IFN-gamma makes the disease worse. They conclude that the CNS inflammatory response is closely linked to, and in some ways dependent upon, the peripheral immune compartment.