The inhomogeneous distribution of MS may represent an important clue about the cause of the disease. The prevalence of MS appears to be increasing in many regions of the world, although it is likely that in a majority of regions surveyed, this increase is attributable to differences in ascertainment over the relatively short period that MS has been surveyed worldwide, which is almost exclusively the last 50 years. MS occurs most frequently in regions populated by northern Europeans, and in these areas, it is much more common in the northern European population than in the indigenous populations. MS occurs in relatives of MS patients at a rate 10- to 50-fold greater than in the general population. On average, the absolute risk to a first-degree relative of an MS patient is 2% to 5%, depending on the exact degree of relatedness. Although the mode of transmission is not certain, a multigenic pattern best fits the observed pattern of transmission. A majority of monozygotic twins are discordant for MS, indicating that a major component of MS susceptibility is environmentally determined, although recent observations in adopted relatives suggest that this risk is not transmissible. Rare epidemics of MS involving small numbers of individuals in geographically isolated regions have been reported. A number of migrant studies suggest that the risk of acquiring MS may be altered by migration, although some also support genetic factors. Analytic approaches to address the role of various risk factors include ecologic studies, case-control studies, and cohort studies. Ecologic studies are best suited for addressing risk factors that influence overall population risk, whereas case-control studies are best suited for addressing risk factors that pertain to individuals within a population. If a risk factor is distributed homogeneously in a given population, a case-control study is insensitive to its effect. Improved methodology to diminish the biases inherent in case-control studies and identification of other important risk factors from basic scientific studies undoubtedly will be important for analytic epidemiologic studies of the future. Furthermore, analysis of highly informative populations, such as discordant identical twins and adoptive siblings of MS patients, likely will improve the specificity of case-control studies by minimizing the vast number of potential differences between cases and controls.