The successful use of B cell depletion therapy for the treatment of autoimmune disease has led to a resurgent appreciation of B cells as powerful regulators of immunity. However, to the surprise of many, B cells appear to regulate autoimmune conditions independently of their ability to produce autoantibodies. Indeed, disturbances in the ability of B cell subsets to present antigen, produce cytokines, and regulate the activities of T cells is emerging as a key feature in many inflammatory diseases. Here we review the recent literature describing cytokine-producing regulatory and effector B cell subsets in health and disease and discuss how future B cell-directed therapies might target the pathologic cytokine-producing effector B cell subsets without impacting the protective regulatory subsets. © 2008 Elsevier Ltd. All rights reserved.