There has been increasing evidence that genetic factors have a role in determining susceptibility to MS. Re-examination of results from prevalence and migration surveys reveals that there remains considerable ambiguity in interpretation. Some patterns previously thought to decisively support environmental determination may still be explained, at least in part, on a genetic basis. It seems inescapable that MS is probably due to an interaction of genetic and environmental factors. It remains undetermined whether or not genes exist which are truly necessary for the development of the disease. Existing data are consistent with the notion that the study of MS susceptibility will parallel the findings in experimental models of spontaneous autoimmunity and that at very least, two genes and almost certainly several genes will be found to influence susceptibility and interact in as yet unknown ways. One of these loci appears to be the Class II MHC, although its role may be minor at the germ line level. Roles for the T-cell receptor alpha and beta loci appear to be minor and may even be non-existent in contributing to heritable susceptibility. We predict that additional loci will be identified which influence both susceptibility and outcome and will be more important. Furthermore, it is clear that the understanding of the contribution of individual susceptibility loci will continue to be difficult because of the constraints of human pedigree data. It is likely that further resolution of the questions posed above related to genetic susceptibility in MS will require multicenter collaboration.