There is a growing body of experimental evidence that B lymphocytes play a central role in the pathogenesis of systemic lupus erythematosus (SLE). B cells are, by definition, the precursors of antibody-secreting cells, and thus are the source of pathogenic autoantibodies. However, recent data indicate that B cells are not merely the passive producers of immunoglobulins, but also play a central role in autoimmunity via nonconventional mechanisms, including autoantigen presentation and modulation of other immune cells. Thus, B lymphocyte depletion has recently emerged as a promising therapeutic approach to the treatment of autoimmune diseases, including SLE. Rituximab is a chimeric mouse-human monoclonal antibody against the B cell-specific antigen CD20, which selectively and profoundly depletes B lymphocytes and has been widely used to treat B cell lymphomas. Recent open-label studies indicate that rituximab is safe and may be efficacious in the treatment of SLE, and continued study with randomized clinical trials is justified.