Extracorporeal photopheresis (ECP) is a well‐tolerated procedure that suppresses T‐lymphocyte activity in a clonally‐specific way. It is an effective therapy that has established indications in the management of cutaneous T‐cell lymphoma, graft‐versus‐host disease and some scenarios of solid‐organ transplant rejection. It is being used increasingly around the world. Its applications are evolving, including exploration of its potential for treating autoimmune diseases where cytotoxic T‐cell‐mediated mechanisms appear to be involved, such as Crohn's disease. This article reviews scientific insights into its mechanism of action on the immune system, details of the clinical procedure, its clinical applications in various diseases, and the current evidence for its efficacy and place in medical therapeutics. J. Clin. Apheresis, 2011. © 2011 Wiley‐Liss, Inc.