Accumulating evidence indicates that multiple sclerosis (MS) is an autoimmune disease mediated by autoreactive T lymphocytes with specificity for myelin antigens. Initially, the evidence to support this hypothesis was based mainly on experiments performed in experimental allergic encephalomyelitis (EAE), the animal model of MS. In this model it was demonstrated that T cells reactive to several myelin antigens are encephalitogenic. Many recent immunological and immunohistochemical studies in MS have yielded further data to support this view. For instance, it was demonstrated that activated myelin basic protein (MBP) and proteolipid protein (PLP)-specific T cells accumulate in the central nervous system (CNS), and that clonally expanded MBP-specific T cells persist for several years in the blood of patients with MS. Furthermore, T cells with specificity for MBP were identified in the brain lesions of the patients. It is not yet clear how these autoreactive T cells are activated in the periphery, but several studies have suggested that viral antigens mimicking the myelin epitopes, or superantigens may be involved. Furthermore, we and others have provided evidence showing that the regulatory mechanisms that control autoreactive T cells in healthy subjects are potentially defective in MS patients. In addition to myelin reactive T cells, B cells producing myelin-specific antibodies and gamma delta T cells may also play an important role in the autoimmune cascade. Based on the recent insights in the disease mechanisms, new experimental therapies were developed to target specifically the pathogenic lymphocytes in MS. Some therapies yielded encouraging data in pilot studies, whereas phase III trials of other drugs showed beneficial effects on the disease course. In this article, we overview the most recent data on the role of autoreactive lymphocytes in the pathogenesis of the disease, and discuss some of the recently developed immunotherapeutical strategies in MS.