Allogeneic hematopoietic cell transplantation is a potentially curative therapy for many malignant and nonmalignant hematologic diseases. Graft-versus-host disease (GVHD) is a common complication after transplantation and remains a major cause of morbidity and mortality, limiting the success of a potentially curative transplant. This paper reviews the current and emerging strategies in GVHD prevention and treatment. New insights are leading the way to the development of novel targeted approaches to minimize the risk of disease relapse and infection. Continued collaborative efforts to conduct high-quality, multicenter clinical trials with standard end points and risk stratification are needed to determine the optimal approach to minimize GVHD and limit toxicities.