Immune tolerance describes specific unresponsiveness to antigens. In clinical situations such as graft-versus-host disease it may be useful to capitalize on these pre-existing tolerance mechanisms to treat patients. Extracorporeal photopheresis is a pheresis treatment whereby the approximately 5 x 10(9) leukocytes are treated with a photoactivatable compound (8-methoxypsoralen) and UVA light, and immediately returned to the patient in a closed-loop, patient-connected system. This therapy induces apoptosis of virtually all the treated leukocytes. There is growing evidence that infusion of apoptotic cells may trigger certain tolerance mechanisms and, thus, be of therapeutic use in graft-versus-host disease. These apoptotic cells are taken up by phagocytes (antigen-presenting cells) in the body of the patient. Apoptotic cell engagement has been reported to induce several changes and functional activities in the engulfing antigen-presenting cell. These antigen-presenting cells: (1) decrease production of proinflammatory cytokines; (2) increase production of anti-inflammatory cytokines; (3) lower ability to stimulate T-cell responses; (4) delete CD8 T effector cells; and (5) induce regulatory T cells. Any and all of these mechanisms could explain the noted effect in graft-versus-host disease. It is still unclear which one or ones are truly responsible. Ongoing studies in animals and human trials will ultimately unravel these details.