B cells and their products, antibodies, play an important role in the diagnosis and, in some instances, in the pathogenesis of many autoimmune diseases. Specific B-cell directed therapies are of recent interest as their impact on B-cell activity can influence a variety of autoimmune diseases. The development and introduction of rituximab, a depleting antibody targeting CD20+ B cells, and previously CD52-directed treatment with Campath-1h for the treatment of B-cell malignancies as well as rheumatoid arthritis have pioneered this therapeutic field. Other non-depleting strategies employ CD22 or B-cell activating factor/B lymphocyte stimulator and apoptosis-inducing ligand as targets and are under clinical investigation at present. Abnormalities of B-cell subsets have been identified by a number of independent groups which often represent characteristic patterns of disturbances of the human B-cell repertoire. However, the clinical value of specific B-cell subset targeting/depletion has not been addressed extensively. As such an approach may afford the possibility to avoid unnecessary adverse events related to depletion of non-pathogenic B-cell populations, B-cell subset targeting may have the capacity to enhance the benefit/risk ratio of B-cell immune intervention.