With the clinical introduction of the anti-CD20 antibody rituximab for the treatment of rheumatoid arthritis (RA), B-cell-targeted therapy has become an accepted strategy for the treatment of a common chronic inflammatory disease. From recently reported synovial biopsy studies, we can begin to develop a pathophysiologic model of the sequential synovial cellular and molecular changes induced by rituximab infusions. These findings may explain how the rapid and early depletion of CD20-bearing B cells may later lead to the more far-reaching histopathologic changes that are associated with clinical responsiveness. Anti-CD20 antibody treatments may therefore affect the representation of not only mature B lymphocytes and differentiated immunoglobulin-secreting cells but also infiltrating cells such as synovial macrophages and fibroblast-like synoviocytes. In light of the known prominence of recirculating memory B cells in RA pathogenesis, we propose that clinical efficacy also in part reflects the development of an effective blockade of the recirculation of potentially pathologic B cells that may prevent reseeding of pathologic synovial ectopic lymphoid tissues.