Two recent genetic studies have identified a critical role for cyclophilin D, a component of the mitochondrial membrane permeability transition pore, in cell death induced by calcium, reactive oxygen species, and cardiac ischemia-reperfusion injury. Transgenic mice lacking cyclophilin D developed normally but showed reduced infarct size after coronary artery ligation and reperfusion. Cells from the knockout mice were resistant to death imposed by excess calcium and H₂O₂, but not to death from x-irradiation, staurosporine, tumor necrosis factor–α, or forced expression of proapoptotic proteins. These data raise questions about the relationship between apoptotic and necrotic cell death, and they also highlight cyclophilin D as a potential therapeutic target in myocardial infarction.