Recent advances have led to the development of mAbs that effectively deplete B cells in human beings and target pathways essential for B-cell development. B cell-directed therapies represent promising treatments for autoimmune disorders, although many questions remain about their optimal use in the clinic. Autoantibody depletion correlates with the clinical effectiveness of these drugs in some diseases but not all. This finding implies that self-reactive B cells are playing important pathogenic roles in autoimmune disorders beyond the production of autoantibodies. Clinical studies of B cell-directed therapies are beginning to illuminate the effects of B-cell modulation on immune function using a variety of mechanistic approaches, including delineation of B-cell subsets by flow cytometry, measurement of serum autoantibodies and cytokines, and tests of immunocompetence. Recent clinical studies have been performed in patients with rheumatoid arthritis and SLE suggesting the depletion of memory cells accounts at least in part for the clinical efficacy of rituximab therapy, but these findings, although provocative, require further investigation in larger cohorts. Memory B cells are not the only targets of depleting antibodies; therefore, other B-cell populations of therapeutic relevance may be modulated by these interventions. Moreover, pathologic B-cell responses may be favorably influenced by other targeted approaches such as those using anti-B-cell activating factor belonging to the TNF family (BAFF) or anti-CD22 antibodies.