Recently, it has been clearly demonstrated that exogenous 1,25-dihydroxyvitamin D-3, the hormonal form of vitamin D-3, can completely prevent experimental autoimmune encephalomyelitis (EAE), a widely accepted mouse model of human multiple sclerosis (MS). This finding has focused attention on the possible relationship of this disease to vitamin D. Although genetic traits certainly contribute to MS susceptibility, an environmental factor is also clearly involved. It is our hypothesis that one crucial environmental factor is the degree of sunlight exposure catalyzing the production of vitamin D-3 in skin, and, further, that the hormonal form of vitamin D-3 is a selective immune system regulator inhibiting this autoimmune disease. Thus, under low-sunlight conditions, insufficient vitamin D-3 is produced, limiting production of 1,25-dihydroxyvitamin D-3, providing a risk for MS. Although the evidence that vitamin D-3 is a protective environmental factor against MS is circumstantial, it is compelling. This theory can explain the striking geographic distribution of MS, which is nearly zero in equatorial regions and increases dramatically with latitude in both hemispheres. It can also explain two peculiar geographic anomalies, one in Switzerland with high MS rates at low altitudes and low MS rates at high altitudes, and one in Norway with a high MS prevalence inland and a lower MS prevalence along the coast. Ultraviolet (UV) light intensity is higher at high attitudes, resulting in a greater vitamin D-3 synthetic rate, thereby accounting for tow MS rates at higher altitudes. On the Norwegian coast, fish is consumed at high rates and fish oils are rich in vitamin D-3. Further, experimental work on EAE provides strong support for the importance of vitamin D-3 in reducing the risk and susceptibility for MS. If this hypothesis is correct, then 1,25-dihydroxyvitamin D-3 or its analogs may have great therapeutic potential in patients with MS. More importantly, current research together with data from migration studies opens the possibility that MS may be preventable in genetically susceptible individuals with early intervention strategies that provide adequate levels of hormonally active 1,25-dihydroxyvitamin D-3 or its analogs.