Summary: Autoimmunity results from abnormal B- and T-cell recognition of self-antigens, which leads to autoantibody production in many cases. Autoantibodies produced by B-cell-derived plasma cells provide diagnostic markers for autoimmunity but also contribute significantly to disease pathogenesis. As discussed in this review, the therapeutic benefit of depleting B cells in mice and humans has refocused attention on B cells and their role in autoimmunity beyond autoantibody production. B cells specifically serve as cellular adjuvants for CD4+ T-cell activation, while regulatory B cells, including those that produce interleukin-10 (B10 cells), function as negative regulators of inflammatory immune responses. The emerging picture is that B cells, autoantibodies, and T cells are all important components of abnormal immune responses that lead to tissue pathology unique to each autoimmune disease, with their relative contributions changing during disease progression. Autoimmune diseases where B-cell functions are closely correlated with disease activity include systemic lupus erythematosus, rheumatoid arthritis, scleroderma, type 1 diabetes, and multiple sclerosis. Understanding the overlapping roles of B cells as mediators of autoimmune disease will facilitate the development of more precisely directed therapies and combination therapies with broader clinical efficacy than current depletion strategies that remove all B cells.