The natural history of MS is highly variable. There is substantial heterogeneity in the clinical manifestations but, at this point, it is reasonable to consider all idiopathic inflammatory demyelinating diseases of the central nervous system as representing a spectrum of the same disease. In large populations, 20% to 40% have "benign disease," defined as having less than moderate disability after 10 years. Benign is a potentially misleading term because many of these patients subsequently will become disabled. Half will develop progressive MS within 10 years and will require some form of walking aid within 15 years following the onset of MS. Survival is not greatly shortened in mildly disabled patients, but the observed mortality is increased four-fold over the general population in patients with advanced disability. Patients with the greatest risk of disability are those with PP MS and RR patients who are older at onset, have pyramidal or cerebellar involvement at onset, and who have frequent or prolonged attacks with incomplete recovery. The biological basis for the variation in the course of MS is understood only in a very limited way. The short- and long-term course of MS may be determined by different biological variables. Short-term benefit in clinical trials should not be assumed to indicate long-term reduction in the risk of permanent disability.