Novel treatment approaches, as potential adjunctive therapy to current reperfusion strategies (such as thrombolysis, primary coronary angioplasty, and cardiac surgery), are required to provide further cardioprotection in the setting of an acute myocardial infarction to effect further reductions in morbidity and mortality. In this regard, the activation of prosurvival kinases, such as Akt and Erk1/2 (which we have termed the reperfusion injury salvage kinase [RISK] pathway), at the time of reperfusion, has been demonstrated to confer powerful cardioprotection against myocardial ischemia-reperfusion injury. In this review, we present evidence suggesting that the cardioprotective phenomena of ischemic preconditioning and the recently described ischemic postconditioning exert their cardioprotective effects through the recruitment of the RISK pathway, at the time of reperfusion, and that the protection in these settings is mediated through the inhibition of mitochondrial permeability transition pore (mPTP) opening at this time. Therefore, the pharmacologic manipulation of the RISK pathway at the time of reperfusion may enable one to harness the powerful cardioprotective benefits of both ischemic preconditioning and postconditioning, and provide a novel approach to cardioprotection.