A large body of immunologic, epidemiologic, and genetic data indicate that tissue injury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develops in genetically susceptible individuals after exposure to an as-yet undefined causal agent. The genetic component of MS etiology is believed to result from the action of several genes of moderate effect. The incomplete penetrance of MS susceptibility alleles probably reflects interactions with other genes, post transcriptional regulatory mechanisms, and significant nutritional and environmental influences. Equally significant, it is also likely that genetic heterogeneity exists, meaning that specific genes influence susceptibility and pathogenesis in some affects but not in others. Results in multiplex MS families confirm the genetic importance of the MHC region in conferring susceptibility of MS. Susceptibility may be mediated by the class II genes themselves (DR, DQ or both), related to the known function of these molecules in the normal immune response, e.g. antigen binding and presentation and T cell repertoire determination. The possibility that other genes in the MHC or the telomeric region of the MHC are responsible for the observed genetic effect cannot be excluded. The data also indicate that although the MHC region plays a significant role in MS susceptibility, much of the genetic effect in MS remains to be explained. Some loci may be involved in the initial pathogenic events, while others could influence the development and progression of the disease. The past few years have seen real progress in the development of laboratory and analytical approaches to study non-Mendelian complex genetic disorders and in defining the pathological basis of demyelination, setting the stage for the final characterization of the genes involved in MS susceptibility and pathogenesis. Their identification and characterization is likely to define the basic etiology of the disease, improve risk assessment and influence therapeutics.