Extracorporeal photochemotherapy (ECP), or photopheresis, is a widely used treatment for cutaneous T cell lymphoma (CTCL) and other T cell-mediated disorders, having been administered in more than 150 centers worldwide more than 200,000 times. Consistent with the theme of this conference--that is, highlighting the potentially most productive investigative avenues for unraveling the mysteries of CTCL in the next decade--ECP has been futuristic since its inception in the early 1980s. In 1988, the treatment was the first FDA-approved selective immunotherapy for any type of cancer. Yet, the mechanism by which it could suppress a clone of CTCL cells or inactivate multiple autoreactive T cell clones in graft-versus-host disease (GVHD) or allograft rejection remained obscure until quite recently. In fact, the scientific principles necessary to begin to comprehend the basis of ECP's efficacy were not available when the treatment was first introduced in 1982. In the intervening years, necessary detailed knowledge of the structure and function of the clonotypic T cell receptors, of class I major histocompatibility complex (MHC) presentation of tumor antigens, of CTCL tumor-specific antigens, of dendritic antigen presenting cell (DC) biology, and of 8-methoxypsoralen immunopharmacology has been attained. Although much remains to be learned, we now appreciate that ECP simultaneously and efficiently induces both apoptosis of disease-causing T cells and conversion of monocytes to functional DCs. By processing and presenting the unique antigenic determinants of pathogenic T cell clones, the DCs can either initiate a clinically relevant anti-CTCL cytotoxic response or suppress the activity of autoreactive T cell clones. This paper will review clinical trials of ECP in CTCL and evolving scientific understanding of ECP's mechanism in the context of exciting future directions.