Mitochondria play an important role in cell death and cardioprotection. During ischemia, when ATP is progressively depleted, ion pumps cannot function resulting in a rise in calcium (Ca²⁺), which further accelerates ATP depletion. The rise in Ca²⁺ during ischemia and reperfusion leads to mitochondrial Ca²⁺ accumulation, particularly during reperfusion when oxygen is reintroduced. Reintroduction of oxygen allows generation of ATP; however, damage to the electron transport chain results in increased mitochondrial generation of reactive oxygen species (ROS). Mitochondrial Ca²⁺ overload and increased ROS can result in opening of the mitochondrial permeability transition pore, which further compromises cellular energetics. The resultant low ATP and altered ion homeostasis result in rupture of the plasma membrane and cell death. Mitochondria have long been proposed as central players in cell death, since the mitochondria are central to synthesis of both ATP and ROS and since mitochondrial and cytosolic Ca²⁺ overload are key components of cell death. Many cardioprotective mechanisms converge on the mitochondria to reduce cell death. Reducing Ca²⁺ overload and reducing ROS have both been reported to reduce ischemic injury. Preconditioning activates a number of signaling pathways that reduce Ca²⁺ overload and reduce activation of the mitochondrial permeability transition pore. The mitochondrial targets of cardioprotective signals are discussed in detail.