Hematopoietic stem cell transplant (SCT) is considered standard therapy for a variety of malignant and nonmalignant diseases. Graft-versus-host disease (GVHD) still represents today a major complication of hematopoietic SCT. Two types of GVHD have traditionally been recognized on the basis of the time of onset following transplantation, distinct pathobiological pathways, and different clinical presentations. The acute form commonly breaks out 2 to 6 weeks after transplantation, affecting up to 60% of patients receiving allogeneic transplants from HLA identical donors. Transfer of immunocompetent donor T cells contained in the graft may undergo alloreactivity against recipient cells because of major or minor histocompatibility antigens disparities between the donor and the immunosuppressed host. Target specificity in acute GVHD involves preferential injury to epithelial surfaces of the skin and mucous membranes, biliary ducts of the liver, and crypts of the intestinal tract. Chronic GVHD affects approximately 30% to 80% of patients surviving 6 months or longer after stem cell transplantation and is the leading cause of nonrelapse deaths occurring more than 2 years after transplantation. Chronic GVHD is a multiorgan syndrome with clinical features suggesting some autoimmune diseases, and possibly both alloreactive and autoreactive T cell clones are involved in its pathophysiology. Although GVHD may convey beneficial graft-versus-leukemia/lymphoma effects, it also entails a significant risk of morbidity and mortality. Patients with mild GVHD need only minimal, if any, immunosuppressive treatment, whereas prognosis of patients with extensive disease or resistant to standard immunosuppressive treatment may be dismal. Early recognition of GVHD followed by prompt therapeutic intervention may prevent the progression to higher-grade disease and improve the outcome for patients receiving hematopoietic SCT.