Immune system dysfunction is common to rheumatic disorders, with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) being classic examples. Altered development and function of B cells may play a prominent role. B-cell abnormalities also occur in other rheumatic diseases, eg, Sjogren's syndrome, Behcet's disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and dermatomyositis. Hence, B-cell depletion has been investigated as a therapeutic option. Clinical trials in RA and SLE have shown that rituximab, an anti-CD20 monoclonal antibody, can profoundly reduce disease activity and is generally well tolerated. Reports of rituximab treatment for ANCA-associated vasculitis and dermatomyositis are also promising. These encouraging results validate the strategy of B-cell depletion in various rheumatic diseases. B-cell depletion with rituximab is under study in larger clinical trials for the purposes of regulatory approval to define more closely its place in RA and SLE treatment paradigms, and smaller clinical trials are ongoing or planned in associated inflammatory diseases.