Multiple sclerosis was at one time viewed as a spiritual (God-given) disorder; only much later was it recognized as a scarring process. With advancing scientific knowledge, it was seen as a primarily demyelinating disease, later as thromboembolic in origin, and finally as inflammatory and destructive, probably an immunologic response to exogenous (infectious) agents or to one or more autoantigens. The pathogenesis of lesions was first ascribed to antibody, later to inflammatory cells, acting via a panoply of mediators, such as cytokines, adhesion molecules, chemokines, and complement components. It is now recognized as a complex disorder, in which many genetically controlled elements interact. Research on model diseases in experimental animals, both autoimmune and initiated by viral infection, has guided research on MS and similar demyelinating disorders of the CNS and PNS.