Brain injury after hypoxic-ischemic encephalopathy often develops with delayed appearance, opening a therapeutic window. Clinical studies in newborns show that post-hypoxic-ischemic hypothermia improves outcome. This has generated renewed interest in the molecular mechanisms of hypoxic-ischemic brain injury. In this brief review, we propose that mitochondrial permeabilization is crucial for injury to advance beyond the point of no return. We suggest that excitatory amino acids, nitric oxide, inflammation, trophic factor withdrawal, and an increased pro- versus antiapoptotic Bcl-2 protein ratio will trigger Bax-dependent mitochondrial outer membrane permeabilization. Mitochondrial outer membrane permeabilization, in turn, elicits mitochondrial release of cytochrome C, apoptosis-inducing factor, second mitochondria-derived activator of caspase/Diablo, and HtrA2/Omi. Cytochrome C efflux activates caspase-9/-3, leading to DNA fragmentation. Apoptosis-inducing factor interacts with cyclophilin A and induces chromatinolysis. Blockage of mitochondrial outer membrane permeabilization holds promise as a strategy for perinatal brain protection.