Mitochondria can serve as the arbiter of cell fate in response to stress. Mitochondrial permeability transition (MPT) is characterized by permeabilization of an otherwise relatively impermeable mitochondrial inner membrane and appears to have a major role in ischemia/reperfusion (I/R) injury in myocardial infarction and stroke. After I/R, the fate of the cell is determined by the extent of MPT. If minimal, the cell may recover; if moderate, the cell may undergo programmed cell death; if severe, the cell may die from necrosis due to inadequate energy production. After reviewing the role of MPT in disease, we examine the signaling and metabolic networks that regulate MPT. We then conclude with some of the challenges in future MPT research.