Over the past decade, considerable attention has focused on the theory that MS is an autoimmune disease mediated by T cells specific for neural autoantigens.’s2 Infectious agents may play a role in triggering an autoimmune process in a susceptible individ~ al,~,~ If so, this would reconcile the roles of environmental and genetic factors in the development of MS. The existence of structural similarities between viral antigens and autoantigens (viral mimicry) and the possibility that viral products (super antigens) can amplify T-cell populations have suggested mechanisms by which an infectious agent such as a virus can initiate an autoimmune process.”‘j An essential element of both hypotheses (molecular mimicry and superantigens) is the expansion and targeting of autoreactive CD4+ T cells to the CNS. Hence, understanding T-cell receptor (TCR) gene usage of autoreactive T cells and their cytokine secretion profile has been a central focus of interest. We propose a model of CNS demyelination that is not predicated upon the continued presence of autoreactive T cells. Instead, we suggest that microglial activation is a central element in CNS demyelination and that the oligodendrocyte-myelin unit is the target. Understanding the nature of microglial activation is likely to offer therapeutic insights to the treatment of MS.