The role B cells and humoral immunity play in multiple sclerosis (MS) is continually evolving. Recent discoveries include advances in lesion classification, identification of B cell clonal expansion in the central nervous system with evidence of antigen targeting, identification of chemokines in MS lesions, and expansion of information on the roles of autoantibodies and complement. Strong indications are accumulating that a greater degree of humoral dysfunction may lead to worsened long-term prognosis in MS. Effects of established MS treatments on B cells and their products have been further defined. Treatments that specifically target B cells are being implemented and hold promise.