Chronic graft-versus-host disease (GVHD) is the major cause of non-relapse morbidity and mortality after hematopoietic stem cell transplant (HSCT). GVHD also is associated with a potent anti-leukemic effect. Chronic GVHD resembles autoimmune diseases and can likely affect any organ or tissue of the body. Skin, oral, liver, and lacrimal gland involvement are most common. The incidence and presentation have been in evolution as new stem cell sources and transplant approaches have been introduced. Although progress in the diagnosis and treatment of chronic GVHD has been limited for many years, there is renewed interest in this disorder. New prognostic scores and animal models of chronic GVHD have been developed. Large, multicenter phase III therapy and biology studies have been undertaken. The challenge for the future will be the discovery of targeted approaches that allow the anti-leukemic effect to be retained and for the reconstitution of normal immunity, thereby reducing infectious complications.