Transplant rejection of solid organs remains a threat to thousands of patients despite modern immunosuppressive regimens. The currently available drugs are associated with severe complications such as hypertension, diabetes mellitus, renal failure, risk of infections, and malignancies among many others and, often enough, still allow episodes of rejection. New and less-toxic immunologic measures are desperately needed to accomplish the desired tolerance to the transplant without the undesirable side effects. Extracorporeal photopheresis (ECP) has been shown to benefit especially patients with cardiac transplants, but also those who received lung allografts. ECP likely modulates the recipient's antigen-specific immune responses and inflammation in transplantation by in vivo generation of apoptotic leukocytes. This review will highlight the need for ECP, how it is thought to act, and the published evidence for its role in cardiac and pulmonary transplantation. J. Clin. Apheresis, 2011. © 2010 Wiley-Liss, Inc.