Photopheresis has become a key component in the therapeutic armamentarium of cutaneous T-cell lymphoma, graft-versus-host disease following stem cell transplant, and allograft rejection of solid organs such as heart. Although it is considered a new treatment modality in its present form, the field of phototherapy dates back thousands of years. In this review, the reader will learn more about the history of photopheresis and how it became a therapeutic alternative for patients with solid organ transplants. An extensive literature search will highlight the evidence-based benefits of photopheresis (or lack thereof). A discussion of the mechanism of action of photopheresis and the technical aspects of the procedure will also be covered. Since photopheresis may be the best tolerated form of immunomodulation, current promising, albeit preliminary data on its efficacy warrant further investigation and understanding.