Self-tolerance is maintained by several mechanisms including deletion (via apoptosis) and regulation. Acquired tolerance to allogeneic tissues and organs exploits similar strategies. One key difference between alloantigens and peptide antigens is the enormous number of T cells that are alloreactive. Accumulating evidence suggests that in the face of this large mass of potentially graft-destructive T cells, tolerance requires an initial wave of deletion. This creates a more level playing field in which a smaller number of regulatory T cells can then act to maintain an established tolerant state. Deletion of alloreactive T cells by apoptosis actively promotes immunoregulation as well, by interfering with proinflammatory maturation of antigen presenting cells. This article reviews the immune response to alloantigens, the development and use of both necrotic and apoptotic means of cell death during the evolution of the immune response, and the likely role and mechanisms by which apoptosis promotes, and may even be required for, transplantation tolerance.