Compelling epidemiological and molecular data indicate that genes play a primary role in determining who is at risk for developing multiple sclerosis (MS), how the disease progresses, and how MS individuals respond to therapy. The genetic component of MS etiology is believed to result from the action of allelic variants in several genes. Their incomplete penetrance and moderate individual effect probably reflects epistatic interactions, post-transcriptional regulatory mechanisms, and environmental influences. Equally significant, it is likely that locus heterogeneity exists, whereby specific genes influence susceptibility and pathogenesis in some individuals but not in others.