Systemic lupus erythematosus (SLE) is a complex disease characterized by numerous autoantibodies and clinical involvement in multiple organ systems. Autoantibodies are usually present in serum for years before the onset of clinical disease. Autoimmunity begins with a limited number of autoantibodies and evolves to become progressively more diverse. Eventually clinical disease ensues. The immunological events triggering the onset of clinical manifestations have not yet been defined. While undoubtedly T cells and dendritic cells appear to play major roles in SLE, a central role for B cells in the pathogenesis of this disease has been brought to the fore in the last few years by work performed both in mice and humans by multiple laboratories. As a result, there is little doubt about the importance of B cells in the development of SLE. Yet much remains to be learned about their role in the ongoing disease process and the merit of targeting B cells for the treatment of SLE. This article will review the role of B cells in human SLE as well as the currently available data on the treatment of SLE by depleting B cells with anti-CD20 (rituximab).