Having evolved to generate a huge Ag-specific repertoire and to mount T cell-dependent responses and long-term memory, the B lymphocyte is a central player in the adaptive branch of immune defense. However, accumulating evidence indicates that B-1 cells of the peritoneal cavity and marginal zone (MZ) B cells of the spleen also can play innate-like immune functions. Their anatomical locations allow frequent Ag encounter. Secreting essentially germline-encoded, polyreactive Abs, and responding rapidly and vigorously to stimulation, these two B cell subsets have evolved to impart potentially protective responses. With their additional capacities to secrete factors that can directly mediate microbial destruction and to express Toll-like receptors (TLR), B cells provide an important link between the innate and adaptive branches of the immune system. Currently, the relevance of these innate-like B cells to the pathogenesis of autoimmune disease is the focus of investigation. In experimental models of autoimmunity, the sequestration of autoreactive B cells in the MZ has been proposed to be essential for the maintenance of self-tolerance. The low activation threshold of MZ B cells makes them particularly reactive to high loads and/or altered self-Ags, potentially exacerbating autoimmune disease. Their expansion in autoimmune models and their association with autoantibody secretion indicate that they may participate in tissue damage. The demonstration that B cell depletion therapies may represent a highly beneficial therapeutic goal in autoimmune disorders suggests that specific elimination of B-1 and MZ B cells may represent a more efficient immunointervention strategy in systemic autoimmunity.