Mitochondria sense and shape cytosolic Ca(2+) signals by taking up and subsequently releasing Ca(2+) ions during physiological and pathological Ca(2+) elevations. Sustained elevations in the mitochondrial matrix Ca(2+) concentration are increasingly recognized as a defining feature of the intracellular cascade of lethal events that occur in neurons during cerebral ischemia. Here, we review the recently identified transport proteins that mediate the fluxes of Ca(2+) across mitochondria and discuss the implication of the permeability transition pore in decoding the abnormally sustained mitochondrial Ca(2+) elevations that occur during cerebral ischemia.