Despite improvements in the practice of allogeneic hematopoietic stem cell transplantation (HCT) over the last 25 years, chronic graft-versus-host disease (GVHD) remains a substantial problem with little change in the incidence, morbidity, and mortality of this complication. In fact, with increased use of peripheral blood, transplantation of older patients, and less immediate transplantation-related mortality, the prevalence of chronic GVHD may increase. One of the difficulties in combating chronic GVHD is a lack of understanding about the pathophysiology of the syndrome. Inherent difficulties in conducting human clinical trials also contribute to the lack of meaningful progress. This review covers potential new approaches to the prevention and treatment of chronic GVHD.