Classically, B-lymphocytes (B cells) are considered to be the mediators of humoral immunity and their role in inflammatory disease largely confined to the down-stream function of antigen-antibody complexes, e.g., in fixing complement and mediating antibody dependent cellular cytotoxicity. More recently, and with the growing acceptance of the view that the immune system operates as an interconnected web of cells and cytokines, a larger role for B cells has been proposed. In this review, with a focus on how B cells and their cytokine products may present novel therapeutic targets, we will briefly discuss B cell ontogeny and discuss the evidence supporting a larger role for B cells in a variety of inflammatory diseases. Special emphasis will be placed on autoimmune diseases. These discussions are intended to provide the reader with the basis for viewing B cells as players of a broader role in inflammatory disease and thus suggest avenues for exploiting B cell directed therapy in novel ways.