There is growing evidence incriminating B lymphocytes in the pathogenesis of graft-versus-host disease (GVHD). Better understanding of the role of B lymphocytes has uncovered new therapeutic approaches, such as CD20 blockade, which appear to be improving outcomes in allogeneic hematopoietic cell transplant recipients. Administration of the chimeric murine/human anti-CD20 monoclonal antibody, rituximab, prior to hematopoietic cell allografting or as part of preparative regimens appears to reduce treatment-related mortality and to improve posttransplant outcomes mainly by decreasing the incidence and severity of acute GVHD. This beneficial effect of rituximab has not had an impact, to the same extent on the incidence of chronic GVHD, which remains a significant cause of morbidity and mortality following hematopoietic cell allografting. Alternatively, rituximab has been shown to be effective for treatment of cGVHD, but data is limited because of the lack of randomized controlled clinical trials and the small sample size in most of the published series. Incorporation of rituximab into the therapeutic armamentarium of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder has clearly improved the overall prognosis of this dreadful disease. This review highlights the evolving role of CD20 blockade in allogeneic hematopoietic cell transplantation and the need to continue to refine B cell depletion strategies in this setting.