In this review, we address current concepts regarding the mechanisms of tissue damage that lead to demyelination and oligodendrocyte loss in multiple sclerosis. Particular emphasis has been placed on examining the MS lesion for evidence for pathogenetic processes that have been implicated from various in vivo and in vitro model systems. Central in this analysis has been the evaluation of the various effector cell types and their products. The results strongly support the conclusion that proinflammatory cytokines are major mediators of tissue damage, through the activation of inflammatory cells and resident glial cells. A role for antibody is also discussed, particularly as part of an antibody-dependent cell mediated demyelinating process. Minor populations of lymphocytes may also participate by defining the nature of the immunological microenvironment.