Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). It is thought that autoimmunity plays a major role in the development of the disease. Despite understanding MS as the cell-mediated autoimmune disease, recent studies suggest a role of humoral response in MS pathogenesis. The contribution of antibodies with anti-MOG specificity in the pathology of EAE (experimental allergic encephalomyelitis), an animal model of MS, in rodents and recently in primates has been demonstrated. B lymphocytes, plasma cells, and autoantibodies reacting with myelin proteins are present in the chronic and active plaques of MS patients. These antibodies, which recognize myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), myelin-oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein (OSP), 2',3' cyclic nucleotide 3'-phosphodiesterase (CNP), and transaldolase (TAL), have been identified mostly in cerebrospinal fluid and in serum. So far, the antibodies directed against MBP, MOG, and OSP have been characterized in detail. However, the role of autoantibodies in MS pathogenesis is still controversial. A direct role in the demyelination process, by the activation of complement and cytotoxic cells, has been shown only for the anti-MOG antibodies. Identification of the antigens and epitopes targeting the autoimmune response in MS is of great importance, not only for understanding of MS pathology, but also for potential therapeutic use. Recently, antigen therapy trials have been conducted in MS patients. It seems, however, that only the recognition of the individual immunological response in each MS patient, including autoantigens and the subspecificity of autoreactive T and B lymphocytes, can allow for an effective fight against this destructive disease.