Mitochondrial ATP generation by oxidative phosphorylation combines the stepwise oxidation by the electron transport chain (ETC) of the reducing equivalents NADH and FADH2 with the generation of ATP by the ATP synthase. Recent studies show that the ATP synthase is not only essential for the generation of ATP but may also contribute to the formation of the mitochondrial permeability transition pore (PTP). We present a model, in which the PTP is located within the c-subunit ring in the Fo subunit of the ATP synthase. Opening of the PTP was long associated with uncoupling of the ETC and the initiation of programmed cell death. More recently, it was shown that PTP opening may serve a physiologic role: it can transiently open to regulate mitochondrial signaling in mature cells, and it is open in the embryonic mouse heart. This review will discuss how the ATP synthase paradoxically lies at the center of both ATP generation and cell death.