Photopheresis or extracorporeal photochemotherapy (ECP) is a novel immunomodulatory therapy based upon pheresis of light-sensitive cells. Whole blood is removed from patients who have previously ingested the photosensitizing agent 8-methoxypsoralen (8-MOP) followed by leukapheresis and exposure of the 8-MOP containing white blood cells (WBCs) extracorporeally to an ultraviolet A (UVA) light source prior to their return to the patient. In 1988, the Food and Drug Administration (FDA) approved photopheresis for the treatment of cutaneous T-cell lymphoma (CTCL). Treatment of CTCL with photopheresis has been reported in over 300 patients worldwide. Photopheresis has also demonstrated encouraging results in the treatment of solid organ transplant rejection, graft versus host disease, scleroderma, and other autoimmune diseases although fewer patients have been studied. This review will focus on the North American experience with photopheresis.