B lymphocytes seem to have a fundamental role in multiple sclerosis, acting as sensors, coordinators, and regulators of the immune response. Furthermore, they are important in activating T cells and they can mediate tissue injury through diverse mechanisms. Such findings have important therapeutic implications in autoimmune central nervous system diseases in a fashion similar to other autoimmune processes. The best known monoclonal antibody targeting B cells that has been used as a novel therapy for various autoimmune conditions, as well as multiple sclerosis, is rituximab. This review summarizes the available data on the role of B cell in multiple sclerosis and further reports on current knowledge on the B-cell-depleting monoclonal antibody rituximab, its mechanism of action, and its efficacy on multiple sclerosis. Data presented were categorized in 3 groups based on the nature of data presented (radiological, clinical, and immunological data). Both case-control studies and case reports were included, while table classification was in chronological order.