Graft-versus-host disease (GVHD) remains a source of significant morbidity and mortality in the setting of allogeneic stem cell transplantation. Improving outcomes in stem cell transplant recipients will require additional therapeutic modalities for GVHD, especially for those patients who fail to respond to initial therapy with steroids. This article provides an introduction to accompanying articles in this issue of Biology of Blood and Marrow Transplantation concerning the current state of GVHD management with an emphasis on the role of extracorporeal photopheresis as a therapeutic modality. Topics discussed include challenges associated with the design of clinical studies of GVHD therapies, the efficacy of and proposed mechanisms of photopheresis in the setting of GVHD, and our emerging understanding of regulatory T cell biology as it relates to allogeneic stem cell transplantation.