Although genetic susceptibility explains the clustering of multiple sclerosis (MS) within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographical variations in MS frequency and the changes in risk that occur with migration, which support the action of strong environmental factors. Among these, vitamin D status, infection with the Epstein-Barr virus, and cigarette smoking are emerging as the most consistent predictors of MS risk. In this article, we review the epidemiological data, critically discuss the evidence for causality of these associations, and briefly discuss the possibility of interventions to reduce MS risk.