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Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS), in which auto-aggressive lymphocytes participate in inflammation that causes myelin destruction. Although T lymphocytes have been viewed as important culprits in the inflammatory cascade that results in MS, clinical trial results and animal model data support a role for B lymphocytes in MS pathology. In spite of these encouraging results, the mechanism behind why B cell depletion might be effective for MS treatment remains unknown. Herein we summarize the state of our knowledge for how B cells and their antibody products may influence the initiation and or propagation of MS, drawing from human studies and animal model data.