Post-mitotic neurons and heart muscle cells undergo apoptotic cell death in a variety of acute and chronic degenerative diseases. The intrinsic pathway of apoptosis involves the permeabilization of mitochondrial membranes, which leads to the release of protease and nuclease activators, and to bioenergetic failure. Mitochondrial permeabilization is induced by a variety of pathologically relevant second messengers, including reactive oxygen species, calcium, stress kinases and pro-apoptotic members of the Bcl-2 family. Several pharmacological agents act on mitochondria to prevent the permeabilization of their membranes, thereby inhibiting apoptosis. Such agents include inhibitors of the permeability transition pore complex (in particular ligands of cyclophilin D), openers of mitochondrial ATP-sensitive or Ca(2+)-activated K(+) channels, and proteins from the Bcl-2 family engineered to cross the plasma membrane. In addition, manipulations that modulate the expression or activity of mitochondrial uncoupling proteins can prevent the death of post-mitotic cells. Such agents hold promise for use in clinical neuroprotection and cardioprotection.