Extracorporeal photopheresis (ECP) is the first FDA approved cellular photoimmunotherapy for cancer and has demonstrated efficacy in T-cell mediated disorders including prevention and treatment of acute and chronic graft-versus-host disease, organ transplant rejection, scleroderma, Crohns disease and diabetes mellitus. Due to its exceptional safety profile ECP has gained wide international acceptance through the efforts of leading clinical investigators. Exciting preclinical data and clinical observations provide insight into the mechanisms of action of ECP and are the basis for further clinical investigations.