Apoptosis is a form of cell death which utilizes energy resources to dismantle and remove cells in an orderly or programmed fashion. It plays an essential role in establishing normal embryonic development, maintaining adult tissue homeostasis and contributes to a variety of human diseases including certain pathological processes in the heart. Apoptosis is mediated by a distinct biochemical pathway that is conserved in multicellular organisms. Signaling for apoptosis is initiated from outside the cell (extrinsic or death receptor pathway) or from inside the cell (intrinsic or mitochondrial pathway). In both pathways, signaling results in the activation of a family of cysteine proteases, named caspases, that act in a proteolytic cascade to dismantle and remove the dying cell. The activation of the intrinsic death pathway involves the release of cytochrome c from the mitochondria and formation of the apoptosome, a catalytic multiprotein platform that activates caspase-9. There is evidence that the mitochondrial pathway is involved in ischemia-induced myocyte apoptosis in the heart. Diminished expression of pro-apoptotic factors and/or expression of certain inhibitors of the apoptosome may raise the threshold for apoptosis in long-lived post-mitotic cells including myocytes of the heart.