Apoptosis or programmed cell death (PCD) is a physiological and pathological process of seminal importance to virtually all systems of the body. Programmed cell death is involved in mechanisms of immune cytotoxicity, immune regulation and ischemia-reperfusion injury processes central to tissue and organ transplantation. To date, PCD has been shown to be involved in diverse areas, including liver and islet graft preservation during procurement and transplant; transplant organ damage and rejection of liver, heart, kidney, islet, and intestine grafts; and immune tolerance. In addition to central tolerance, at least two systems of peripheral immune tolerance, the veto cell mechanism and the costimulation blockade, clearly involve PCD. Virtually all well studied systems generating immunodeviation and normal immunoregulation depend to some degree on PCD. Thus, the potential for therapeutic immunomodulation using PCD-directed therapy is enormous. Progress in understanding crucial mechanisms of PCD, such as caspase activity, proteosome function, and Fas/Fas ligand, TRAIL-R/TRAIL, and TNF/TNFR-1 and -2 signaling pathways, as well as mechanisms of inhibition of both type I and type II pathways of PCD among the various functional immune cells, will be critical for targeting future immunomodulation therapies for transplantation.