Multiple sclerosis (MS) was previously thought to be a T-cell-mediated, demyelinating disease of the central nervous system. Disease-modifying therapies targeting T cells have, indeed, shown remarkable efficacy in patients with relapsing-remitting MS. However, these therapies do also target B cells, and a B-cell-depleting monoclonal antibody (ocrelizumab) has recently been approved for MS therapy and is efficacious not only in relapsing forms of MS but also in some patients with primary progressive MS. This suggests that B cells may play a more important role in the pathogenesis of MS than previously appreciated. We review the potential roles of B cells, which are the precursors of antibody-secreting plasma cells in the pathogenesis of MS. Furthermore, we provide an overview of the characteristics and clinical data for the four monoclonal antibodies (ocrelizumab, ofatumumab, rituximab, and ublituximab) that have been approved, are currently been used off-label or are being investigated as treatments for MS. These antibodies all target the cluster of differentiation (CD)-20 molecule and bind to distinct or overlapping epitopes on B cells and a subset of T cells that express CD20. This leads to B-cell depletion and, possibly, to depletion of CD20-positive T cells. The net result is strong suppression of clinical and radiological disease activity as well as slowing of the development of persisting neurological impairment.