Objective: To evaluate the use of rituximab in the clinical management of steroid-refractory chronic graft-versus-host disease (GVHD). Data Sources: Literature was accessed through MEDLINE and International Pharmaceutical Abstracts (1990–September 2008), both indexed and nonindexed citations, using the terms rituximab, graft-versus-host disease, monoclonal antibodies, and CD20. In addition, reference citations from the publications identified were reviewed. Study Selection and Data Extraction: All articles discussing rituximab as a therapeutic option in the treatment of GVHD that were published in English and enrolled human study participants were evaluated. Data Synthesis: Rituximab is a genetically engineered chimeric murine monoclonal antibody that binds to the CD20 differentiation antigen found on B-lymphocytes. GVHD is the leading cause of procedural-related morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Chronic GVHD (cGVHD) occurs in up to 70% of individuals undergoing HSCT, and approximately 40% of those patients are refractory to conventional T-lymphocyte–directed therapies. Limited treatments are available for individuals with steroid-refractory cGVHD. Rituximab therapy in individuals with extensive cGVHD has demonstrated clinical efficacy with manageable toxicities in retrospective and prospective studies. Conclusions: Available data suggest that rituximab is a treatment option for patients with extensive steroid-refractory cGVHD. Rituximab may be particularly effective for individuals with steroid-refractory cGVHD manifesting as thrombocytopenia or with sclerodermatous, cutaneous, and rheumatologic involvement.