As more and more patients undergoing allogeneic hematopoietic SCT (HSCT) survive the early post-transplant period, the number of individuals at risk for chronic GVHD has grown. Treatment for established cGVHD remains unsatisfactory. No experimental agent has demonstrated superiority to steroids alone in a randomized clinical trial. Distinguishing chronic from acute graft-versus-host disease is a major issue. The importance of achieving clarity in cGVHD diagnosis is critical as efforts are undertaken to understand its pathogenesis and to design definitive trials that can target prevention and/or treatment. Immune tolerance to self-antigens may be broken in cGVHD, giving rise to the autoimmune manifestations of the disorder. Recent attention has focused on CD4+CD25 regulatory T cells and their relationship to cGVHD. Significant enthusiasm has emerged for manipulating Treg either ex vivo or in vivo for clinical benefit. Another immunomodulatory approach to cGVHD might be the targeting of B lymphocytes and the antibodies they produce. As efforts continue to devise strategies to treat and prevent chronic GVHD, it is important to acknowledge the link between cGVHD and freedom from relapse, at least for certain malignancies.