A large body of immunological, epidemiological, 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. A genetic component in MS is indicated by an increased relative risk to siblings compared to the general population, and an increased concordance rate in monozygotic compared to dizygotic twins. The past few years have seen real progress in defining the genetic basis of MS setting the stage for new approaches for the final characterization of the genes involved in MS susceptibility and pathogenesis. Whole genome screens conducted in different populations identified discrete chromosomal regions potentially harboring MS susceptibility genes, however, with the exception of the Major Histocompatibility Complex (MHC) on 6p21, no single locus generated overwhelming evidence of linkage. These results suggest a complex genetic etiology, including multiple genes of small to moderate effect and probable genetic heterogeneity. The identification and characterization of MS susceptibility genes and their correlation with disease phenotypes is likely to define the basic etiology of the disease, improve risk assessment, and influence therapeutics.