Photopheresis, the process by which peripheral blood is exposed in an extracorporeal flow system to photoactivated 8-methoxypsoralen (8-MOP), is a new treatment for disorders caused by aberrant T lymphocytes. It is now a standard therapy for advanced cutaneous T-cell lymphoma and shows promise in the treatment of two autoimmune disorders, pemphigus vulgaris and progressive systemic sclerosis (scleroderma). Additional diseases for which clinical trials are in progress include multiple sclerosis, organ transplant rejection, rheumatoid arthritis, and AIDS. The mechanism of action appears to involve a "vaccination" against the pathogenic T cells, in a clone-specific manner. Photoactivated 8-MOP initiates a cascade of immunologic events by forming covalent photoadducts with nuclear and cell surface-adherent DNA and possibly with other cellular molecules. For reasons not yet fully clarified, but probably related to enhanced cycling of the T-cell receptor for antigen, photopheresis increases the immunogenicity of the irradiated T cells so that their reinfusion induces a therapeutically significant immunologic reaction that targets unirradiated T cells of the pathogenic clone(s). The specificity of the induced immunologic reaction probably results from the extremely disproportionate expansion of the pathogenic clone(s), relative to the several million other clones of normal T cells.