The B lymphocyte-associated antigen CD20 is becoming an important immunotherapy target for autoimmune diseases, although its biological function has not been defined. Besides rheumatoid arthritis, growing experience with B cell-depleting therapy indicates that it may be effective in Sjögren's syndrome, dermatomyositis-polymyositis, systemic lupus erythematosus and some types of vasculitides. However, controlled clinical trials are still lacking for some of these indications. Infection has not been seen as a major limitation to this therapy, but reports of progressive multifocal leukoencephalopathy in an extremely small number of patients are of concern. Here, we review the therapeutic actions of anti-CD20 antibodies, and the recent and ongoing clinical trials with CD20-depleting therapy in autoimmune diseases.