PURPOSE OF REVIEWGraft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), despite improvements in our understanding of its pathophysiology as well as the generation of new monoclonal antibodies, immunomodulatory chemotherapy, cellular therapeutics and supportive care. Herein, we review therapies that have proven effective as well as newer agents that have recently improved GVHD response rates and survival following HCT. RECENT FINDINGSNovel approaches to prevent or treat GVHD are often based on evidence from experimental models. Our understanding of the pathophysiology of GVHD may lead to the development of innovative strategies that target both soluble and cellular effectors. Among such agents are sirolimus, anti-tumor necrosis factor antibodies, anti-LFA-3–IgG fusion protein, extracorporeal photopheresis, mesenchymal stem cells and regulatory T cells. SUMMARYObstacles to the improvement of HCT include the tight linkage between GVHD toxicity and the beneficial graft-versus-leukemia (GVL) effect, as well as the impairment of immune reconstitution by immunomodulatory drugs leading to life-threatening infections. The design of newer phase I/II clinical trials are underway. Future therapies are likely to include modulation of cell types that play key roles in the GVH process, including regulatory T cells, dendritic cells, natural killer T cells and B cells.