Extracorporeal photopheresis or chemophototherapy (ECP) is a current therapy and concept that has demonstrated clinical efficacy in the treatment of acute and chronic graft versus host disease (GVHD), Sezary syndrome or cutaneous T-cell lymphoma (CTCL) and organ transplant rejection. Patient inclusion in ECP protocols increases due to the diffusion of technical progress but has to be explored regarding various schedules and processes. ECP mechanisms of action are still unclear despite evident implication of a complex cascade beginning from the apoptosis of the various cell types collected and exposed to the process that is followed by an immunomodulation via antigen presentation. Exploration of the mechanisms in animal models has many limits that weakness human clinical link. Beside major indications, the barrier to ECP treatment extension is the absence of randomized trials in comparison to alternative therapies. The cost of ECP treatment is also a limitation and has to be evaluated relative to other strategies. Nevertheless, the efficacy and the absence of major side effects deserve attention, mainly for the extension of the ECP treatment in clinical trials as new therapeutic line.