Rituximab is a chimeric monoclonal antibody directed against CD20, a B-cell antigen expressed on B-cell lymphoma. It is widely used as single agent for the treatment of follicular lymphoma or in conjunction with other combination therapy as frontline or salvage therapy. Its efficiency in B-cell depletion has lead to other applications such as therapy for autoimmune diseases, GVHD and other immunologic complications in allogeneic stem cell transplantation. Clinical responses to rituximab unveiled the role of B-cells in the pathogenesis of these disorders. Attenuation of pathogenic antibody production partly explained the clinical response in patients with autoimmune disease and chronic GVHD, but other immune mechanisms might be operative as well. Expansion of regulatory T-cells (Tregs) following rituximab therapy indicated the interaction of T- and B-cells in chronic GVHD. Therefore, effort to maintain expansion of Tregs might be important for long-term control of these diseases. Other B-cell targeting strategy directing against B-cell-activating factor (BAFF) or its receptor could be considered in conjunction with rituximab. Recent CIBMTR data on reduced cumulative incidence of acute GVHD in patients who had prior rituximab also suggest the early role of B-cells in allogeneic transplantation, thus opening the opportunity for further immune modulation to prevent acute GVHD.