There is growing recognition that B cell contributions to normal immune responses extend well beyond their potential to become antibody-producing cells, including roles at the innate–adaptive interface and their potential to modulate the responses of other immune cells such as T cells and myeloid cells. These B cell functions can have both pathogenic and protective effects in the context of central nervous system (CNS) inflammation. Here, we review recent advances in the field of multiple sclerosis (MS), which has traditionally been viewed as primarily a T cell–mediated disease, and we consider antibody-dependent and, particularly, emerging antibody-independent functions of B cells that may be relevant in both the peripheral and CNS disease compartments.