In recent years, there has been a significant increase in the therapeutic options available for the management of relapsing forms of MS. Therapies primarily targeting B cells, including therapeutic anti-CD20 monoclonal antibodies, have been evaluated in phase I, phase II, and phase III clinical trials. Results of these trials have shown their efficacy and relatively tolerable adverse effect profiles, suggesting a favorable benefit-to-risk ratio. In this review, we discuss the pathogenic role of B cells in MS and the rationale behind the utilization of B-cell depletion as a therapeutic cellular option. We also discuss the data of clinical trials for anti-CD20 antibodies in relapsing forms of MS and existing evidence for other B-cell–directed therapeutic strategies.