Although the evidence of involvement of viruses in the pathogenesis of MS is largely circumstantial, the pattern of association is constant, with little evidence for direct viral infection of the CNS but with a consistent immune response to several common viruses. In parallel with these studies, epidemiological studies, while indicating genetic predisposition, favor an environmental pathogenetic factor and experimental models indicate that viruses can induce demyelination either by oligodendrolysis or by a variety of immune mechanisms with or without persistence in the CNS. In elucidating the pathogenesis of MS, the challenge is to understand the basis of the immune abnormalities, with intrathecal synthesis of viral antibodies and abnormal immune responses to some viruses, and to relate these to the MRI abnormalities which indicate periodic BBB breakdown. There is strong evidence that the breakdown is associated with inflammation. and that cytokines, particularly TNF, may play a role in demyelination. In conclusion, therefore, several factors are probably key in our understanding of MS. These include: (i) the genetic control of the immune system and its interaction with viral antigen; (ii) related effects on cerebral endothelium including cytokine and adhesion molecule regulation; and (iii) associated glial and axonal responses. Such an approach to the pathogenesis of MS may not identify a specific cause. It may, however, indicate that a pathological cascade can be "triggered" by several common viral infections and that therapy can be used to intervene at several points in the pathological response.