This chapter provides an overview of treatments targeting B-cells and humoral responses in multiple sclerosis (MS). Intravenous Ig (IVIg) and plasma exchange (PLEX) action provide successful treatment of active MS relapses or prevention of relapses. Rituximab has been evaluated for its potential to treat autoimmune states in which B-cells and autoantibodies have been thought to contribute to disease pathophysiology. Ocrelizumab is a humanized anti-CD20 monoclonal antibody (IgG1) that recognizes an epitope that overlaps with that recognized by rituximab. Ofatumumab targets an epitope different from rituximab and most other anti-CD20 antibodies. The initial pursuit of clinical trials with rituximab in MS was based on the consideration that such an approach would serve to decrease precursors to plasma cells, thereby reducing synthesis of potentially pathogenic central nervous system (CNS)-directed antibodies. The success of B-cell depletion in MS has opened the door to a therapeutic strategy.