Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation (HCT). GVHD occurs in acute and chronic forms. Acute GVHD usually manifests within 100 days following HSCT. It is induced by donor T cells responding to the mismatched host polymorphic histocompatibility antigens. Chronic GVHD generally manifests later (>100 days) and has some features of autoimmune diseases. It may develop either de novo or following resolution of - or as an extension of - acute GVHD. Chronic GVHD is also thought to be induced by donor T cells, but the nature of relevant antigens, the critical cellular subsets and the mechanisms of chronic GVHD remain less well understood. In this chapter we briefly discuss and contrast the pathophysiologies of acute and chronic GVHD.