Strategies for treating autoimmune disorders are increasingly employing targeted therapies rather than non-specific, multitargeted treatments. Accumulating evidence on the involvement of B lymphocytes in the pathophysiology of autoimmune demyelinating disease has led to a renewed interest in B cells as potential therapeutic targets. In particular, antigen presentation between B cells and T cells, increased trafficking of B cells across the blood-brain barrier, and autoantibodies produced by plasma cells may contribute to the pathophysiology of autoimmune disorders such as multiple sclerosis. Several B-cell-targeted, depletion therapies are currently in development, including rituximab, epratuzumab, diphtheria toxin-single chain Fv (DC2219), belimumab, atacicept, abatacept, and abetimus sodium. Of these agents, only rituximab and abatacept have been evaluated in multiple sclerosis patients. Preliminary results of a phase II trial of rituximab in multiple sclerosis suggest that rituximab is well tolerated and significantly reduces the number of gadolinium enhancing lesions over 24 weeks of treatment. Results of an exploratory analysis suggest the potential promise of abatacept 10 mg/kg for multiple sclerosis. It is expected that future clinical trials will establish a role for B-cell-targeted therapies in the treatment of multiple sclerosis and other autoimmune neurological diseases. This article describes the mechanism of action behind B-cell-targeted depletion therapies in development and reviews available clinical data.