Although in developed countries, the rates of cardiovascular mortality show a decreasing trend, both the incidence and the prevalence of cardiovascular disease are on the rise in developing countries. It is likely that the currently unfolding epidemics of diabetes and obesity will erode recent gains in decreasing cardiovascular mortality in the Western countries as well. This article will focus on recent research which suggests that induction of mitochondrial permeability transition (MPT) during ischemia/ reperfusion (I/R) injury is a critical event that triggers both necrotic and apoptotic cell death. Additionally we will examine mechanisms that limit or prevent MPT which may be targeted to decrease ischemic cell death and to promote postischemic recovery of the heart. Nevertheless, the role of the mitochondria in myocardial I/R injury is complex and the signal transduction mechanisms that regulate MPT and its downstream consequences remain unclear and represent the current focus of several strategies of cardioprotection. Decades of exploration of the mitochondrial domains and the role of these organelles in regulating cell death and ischemic injury have brought us to a place where clinical interventions to limit infarct size seem to be realizable possibilities. The purpose of this review is to examine the possibility that inhibition of MPT may provide a clinically relevant target for decreasing I/R injury. Understanding MPT provide new insight into the role mitochondria play in decisions of cell survival and death.