Approval of the anti-CD20 antibody rituximab for the treatment of moderate-to-severe rheumatoid arthritis in patients who fail to respond to anti-tumor-necrosis-factor agents has raised interest in B-cell-directed therapy for this disease. A number of direct and indirect modalities with distinct mechanisms of action are being investigated, including anti-CD20 and anti-CD22 therapies, and new approaches for blocking members of the tumor necrosis factor cytokine family including B cell activating factor (BAFF) and a proliferation ligand (APRIL), which are at late stages of clinical development. Clinical experience is most extensive with rituximab, and suggests that targeting 'autoimmune' memory B cells is a feasible approach for treating autoimmune disease. Although anti-CD20 therapy has only been approved for rheumatoid arthritis thus far, data suggest this approach could be valid for other autoimmune diseases, including systemic lupus erythematosus, Sjögren's syndrome, vasculitides, autoimmune cytopenias, and neurologic and dermatologic autoimmune diseases. Additional studies of direct and indirect B-cell-directed treatments are needed before we can draw conclusions as to the value of this approach in patients with various autoimmune diseases and whether more precisely defined techniques than these are required to target the complex humoral system effectively.