Postconditioning has recently been described as a powerful cardioprotection that prevents lethal reperfusion injury. Growing evidence suggests that mitochondrial permeability transition may be a key event in postconditioning. This proposition arises from the complementary observations that: (1) conditions for the mitochondrial permeability transition pore (mPTP) opening are built up during early reperfusion, (2) mPTP opens at the time of reperfusion, (3) transgenic structural alteration of mPTP modifies its opening probability following ischemia-reperfusion, (4) mPTP plays a role in preconditioning, and (5) postconditioning attenuates lethal reperfusion injury. We review in this article current evidence for an important role of the mitochondrial transition pore in postconditioning.