Over the past decade there has been considerable progress in elucidating the signaling pathways involved in cardioprotection. Considerable recent data suggest that many of these signaling pathways converge on the mitochondria, where such pathways alter the activity of key mitochondrial proteins, leading to reduced apoptosis and necrosis. Inhibition of the mitochondrial permeability transition pore is emerging as a central mechanism in cardioprotection. This review focuses on mechanisms by which cardioprotection alters mitochondrial proteins and channels that regulate cell death and survival.