The past few years have seen a surge of interest in B cell depletion therapy for patients with rheumatoid arthritis. This paper outlines the possible mechanism(s) by which B cell depletion therapy works. It is likely there is more than one mechanism and the relative importance of each mechanism depends on the target cell. These include CD20-induced apoptosis, complement dependent cytotoxicity, antibody dependent cell-mediated cylotoxicity, and selective targeting and depletion of B cell subsets. The implications of these mechanisms in the further improvement of B cell depletion therapy in rheumatoid arthritis and other autoimmune diseases are discussed.