The design of effective prevention strategies for multiple sclerosis (MS) is hampered by ignorance of the basic pathophysiology of the disease. An understanding of specific immune mechanisms, the nature of genetic susceptibility, and environmental triggers will permit rational decision making from among the many proposed therapeutic directions available. It is reasonable to hypothesize that inhibition of central nervous system inflammation will be of benefit in MS, regardless of the trigger (autoantigen, exogenous antigen, or nonspecific trigger). Emerging concepts are reviewed to provide guideposts for the design of rational therapy for MS.