Extracorporeal photopheresis (ECP), a modality that exposes isolated white blood cells to photoactivatable 8-methoxypsoralen and UVA light ex vivo followed by returning the treated leukocytes to the body, is used for the treatment of cutaneous T cell lymphoma, graft versus host disease and some other T-cell-mediated diseases. However, the disadvantages of this therapy include the destruction of both diseased and normal T cells with little selectivity, and clinically, long-lasting, expensive and only partial response in the majority of treated patients. Furthermore, the mechanism of action is not fully understood, so that it makes difficult to broaden application to additional types of T-cell-mediated diseases. Selective, short duration, cheap and more effective alternatives are thus needed. Our previous studies over a 30-year period have established a broad biological basis for introducing a new concept of ECP technology with the potent photosensitizer protoporphyrin IX derived from its precursor, 5-aminolevulinic acid (ALA) (Gliolan, photonamic, GmbH & Co. KG, Germany). The use of ALA for ECP may cause selective and effective immunogenic cell death of proliferative malignant or activated T-cells without compromising functions of the normal T-cells to induce systemic anti-disease immunity. Our ongoing preclinical and clinical studies will be presented.