Pathological examination of the affected human tissue is key to understanding the possible mechanisms operating in the disease. In multiple sclerosis (MS), studies of central nervous system (CNS) tissues reveal the inflammatory nature of the disease associated with demyelination and axonal damage. Based on the concept of a pathogenic adaptive immune response, immunosuppressive therapies have been developed in an attempt to block or inhibit the potentially pathogenic T and B cells. More recently, re-examination of the neuropathology has led to a resurgence of interest in the neurodegenerative aspects of the disease, the involvement of cortical damage as well as the role of innate immunity in MS. These ideas have led to paradigm shifts from MS being the result of autoimmunity to myelin due to initial adaptive immune responses, to that of a neurodegenerative disease in which, besides T and B cells, innate immunity may play a major role in the disease process. The neuropathological studies have undoubtedly influenced pharmaceutical interest in development of neuroprotective approaches. Here we review the latest findings from pathological studies of MS tissues and discuss the relevance of these findings for future therapeutic approaches.