Ischemic preconditioning (PC) and postconditioning (PostC) are endogenous mechanisms of protection of the ischemic heart. In brief, short cycles of sublethal ischemia separated by brief periods of reperfusion render the heart resistant to infarction from a subsequent lethal episode of prolonged ischemia. Although PC is a powerful form of protection, its clinical application is limited because of ethical and practical reasons. It is of interest that multiple very short periods of ischemia and reperfusion applied at the onset of reperfusion are also capable in limiting the infarct size. In fact, the short ischemic insults in PC have to be applied before the onset of sustained period of ischemia which cannot be precisely anticipated. On The contrary, the very brief insults in postconditioning (PostC) have to be applied immediately after the end of the long ischemia thus making the intervention more easily applicable. Both mechanisms reduce the infarct size by limiting the reperfusion injury. Pharmacological PC and PostC represent ideal alternatives that may substitute the short ischemic insults for pharmaceuticals means. The components of PC share two pathways, one that involves the mitochondrial KATP channels- free radicals and PKC and another one that involves adenosine and PKC. Reperfusion injury salvage kinases (RISK) prevent the mitochondrial permeability transition pores (mPTP) which destroy the mitochondria and cause cell death. PC via PKC and PostC via gradual restoration of pH at reperfusion up-regulate RISK and preserve viable part of the ischemic region of the heart. In order to confer pharmacological protection, novel therapeutic strategies, based on the knowledge of the ligands, of the receptors and of the intracellular signaling pathways have emerged. Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. Furthermore, agents that increase RISK or directly prevent mPTP are also under investigation as PostC analogues. We summarize recent studies focused on the pharmacological interventions and on the discovery of novel agents that may reduce the infarct size.