This chapter reviews some of the current investigations regarding the neuropathology of multiple sclerosis (MS). To an increasing degree, immunocytochemical methods are being used to extend the recognition of cellular activities, particularly of the immune system, in the lesions and surrounding tissues. To some extent, these studies are associated with electron-microscope observations. The blood-brain barrier is the site of the first pathologic events, but it is still unclear as to what initially opens the barrier, or how. As regards the demyelinative process itself, the general impression now is that the primary target of the attack by the disease process is the myelin sheath, not its parent cell, the oligodendrocyte. Uncertainty still exists as to the status of oligodendrocytes in MS. Some, but not all, survive. Remyelination regularly occurs early in MS lesions, but it is ineffective. Many neuropathologic questions remain unanswered and require further research.