Systemic lupus erythematosus (SLE) is a complex immune disorder in which loss of tolerance to nucleic acid antigens and other cross-reactive antigens is associated with the development of pathogenic autoantibodies that damage target organs including the skin, joints, brain, and kidney. B cells are essential to lupus pathogenesis, not only because they produce pathogenic autoantibodies but also because they have multiple effector functions in the immune system. There has been much recent interest therefore in targeting of B cells for the treatment of SLE and other autoimmune diseases. BAFF (B-cell activation factor belonging to the tumor necrosis factor family) is a crucial homeostatic cytokine for B cells that is upregulated during inflammation and links adaptive with innate immunity. Excessive levels of BAFF may alter selection of autoreactive B cells and contribute to perpetuation of SLE by a variety of mechanisms. BAFF antagonists have been effective in the prevention and treatment of SLE in several different murine models. Three classes of BAFF antagonists have been developed for clinical use, and initial clinical trials have begun. However, immune modulation in SLE is complicated by differences in the immune defects between patients and at different disease stages. Further work will be needed both in animal models and humans to determine the most appropriate clinical applications for BAFF blockade.