This chapter focuses on autoimmunity in multiple sclerosis (MS). MS is a common cause of neurological disability in middle-aged adults. Age, sex, race, geographical latitude, genetics, and environmental exposure are risk factors for developing MS. The risk for developing MS within dizygotic twins is the same as for other siblings. Not only genetic but also one or more exogenous or environmental factors may influence the development of MS. Loss of myelin due to inflammation with limited subsequent remyelination are the two cardinal features of MS. Breakdown of the blood-brain barrier is typically observed with early inflammatory changes. Immunocytochemical studies of active MS lesions show damage to vascular walls with intramural deposition of complement on smooth muscle components and protein-rich leakage. Epidemiology, pathophysiology, and etiology of MS are discussed in the chapter.