Multiple sclerosis is a chronic inflammatory condition of unknown cause. Increasing evidence suggests that the disease develops as a result of interactions between the environment and the immune system in genetically susceptible individuals. It has long been recognized that infections may serve as environmental triggers for the disease, and a large number of pathogens have been proposed to be associated with multiple sclerosis. Here, we detail the historical basis linking infections to multiple sclerosis and review the epidemiology of the disease, which suggests a possible relationship with infectious agents. We also describe pathophysiologic studies in animals and other human demyelinating diseases that have demonstrated a variety of mechanisms by which infectious agents may induce chronic, relapsing central nervous system disease with myelin damage and relative preservation of axons, similar to multiple sclerosis. In addition, we discuss recent studies in individuals with multiple sclerosis indicating enhanced immune responses to infectious antigens, though not consistently demonstrating evidence for ongoing infection. Taken together, these studies suggest a role for infectious agents in the development of multiple sclerosis. Conclusive evidence, however, remains lacking.