Apoptosis is crucial for normal lymphocyte homeostasis and for the maintenance of self-tolerance. However, the role of apoptosis in the induction of transplantation tolerance has been unclear. Recent data now strongly suggest that the apoptotic deletion of T cells is an absolute requirement for the induction of peripheral tolerance to major histocompatibility complex–mismatched organ transplants. The authors propose that apoptosis may control acute graft rejection by reducing the size of the allodestructive T-cell pool, whereas the anti-inflammatory effects of apoptotic cell debris may facilitate the maintenance of tolerance by favoring the development of an active immunoregulatory state.