Extracorporeal photopheresis (ECP) is a therapeutic intervention for modulating immune responses using an autologous apoptotic cell-based product, known as a photopheresate. The process of generating photopheresates offers attractive possibilities for manipulating distinct leukocyte subsets to either augment or dampen immune responses, depending on the disease context. This review discusses current uses of ECP as a cell-based therapy and introduces possible strategies to enhance the potency of photopheresates. In Europe, ECP is regulated under the European Union Tissue Directive, but innovative applications in solid organ transplantation, including modifications of the procedure, may force its reclassification as an Advanced Therapy Medicinal Product. Such modifications might include loading dendritic cells with antigens, polarizing dendritic cells toward immunogenic or tolerogenic states, or genetically manipulating leukocyte subsets. In conclusion, although ECP is a long-established, safe, and effective therapy, the more rigorous standards applied to Advanced Therapy Medicinal Product manufacture could help to ensure the quality of photopheresates applied to solid organ transplant recipients.