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Despite current standard preventive strategies that include optimizing donor selection and the combination of methorexate and a calcineurine inhibitor, acute and chronic GVHD remains a major barrier to successful hematopoietic cell transplantation for a sizeable proportion of patients. When acute and chronic GVHD become manifest a standard primary therapy approach has been the addition of glucocorticoid therapy to a background of calcineurine inhibition. When this approach fails patients with GVHD require secondary therapy. Ideally, second-line agents should promote transplantation tolerance so that the morbidity associated with prolonged use of glucocorticoids and other immunosuppressive agents can be minimized. Promising new agents or strategies which warrant further controlled clinical trials include: mycophenolate mofetil, sirolimus, humanized or chimeric monoclonal antibodies such as visilizumab, daclizumab and infliximab, and extracorporeal photopheresis. Co-operative studies are necessary to hasten the process of evaluating novel treatment strategies for acute and chronic GVHD.