Pathology studies of the central nervous system (CNS) tissues from multiple sclerosis (MS) heavily rely on post-mortem tissues obtained from patients with long-standing disease. MS can be classified as an acquired inflammatory demyelinating disorder. The pathology resembles infectious demyelinating disease and indeed MS is suspected to have viral etiology, but this is still not proven. This chapter discusses the pathology of the subtypes and classical forms of MS as well as several closely associated inflammatory demyelinating disorders. The study of early MS has led to the classification of four patterns of lesions assumed to be due to heterogeneous mechanisms of demyelination. The CNS is protected by the blood-brain barrier (BBB), the blood-spinal cord barrier (BSCB), and the blood-cerebrospinal fluid (CSF) barrier (BCB). Pathological studies have revealed an important and major contribution of neurodegeneration giving rise to the hypothesis that MS may be classified as a neurodegenerative disease.