Humans are protected from a daily onslaught of pathogenic organisms by an immune system that provides multiple layers of protection. Until solid organ transplantation became technically feasible in the early twentieth century, this constant state of surveillance for foreign cells that are associated with the immune response mostly was viewed as advantageous. Unfortunately for patients who have end-stage failure of heart, lungs, kidney, liver, and pancreas, the immune system is incapable of distinguishing between the presence of beneficial foreign tissue and harmful foreign pathogens; it mounts an effective attack against both. Improving our understanding of the factors that initiate and perpetuate the alloimmune response will result in the development of more refined and better tolerated immunosuppressive strategies.