The opening of the mitochondrial permeability transition pore (PTP) has been proposed to play a critical role in activating cell death in many settings, including cardiac ischemia and reperfusion. Although the identity of pore forming unit of the PTP is still debated, it is generally agreed that cyclophilin D (CyPD) is a regulator of the PTP. This manuscript will focus on understanding how CyPD might regulate the PTP and how understanding CyPD might give insight about the identify and regulation of the PTP.