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This chapter briefly summarizes the history of pediatric multiple sclerosis (MS) and related diseases, and current clinical and research directions. Pierre Marie observed that MS in children might be related to acute infectious diseases, syphilis or trauma, suggesting that there was some overlap with infectious or post-infectious central nervous system (CNS) diseases such as acute disseminated encephalomyelitis (ADEM). The reported cases of MS in children may have, in fact, been leukodystrophies. ADEM is classically described as monophasic illness, and one that predominantly occurs in childhood, as opposed to MS, a relapsing and remitting disease, which predominantly occurs in young adults. The study of pediatric MS provides a unique opportunity to examine factors contributing to MS pathogenesis in general, since in affected children there is a close temporal proximity between the interplay of biological, genetic and environmental factors leading to clinical expression of the disease.