Despite tremendous advances in cardiovascular research and clinical therapy, ischemic heart disease remains the leading cause of serious morbidity and mortality in western society and is growing in developing countries. For the past 5 decades, many scientists have studied the pathophysiology of myocardial Ischemia Reperfusion (I/R) injury leading to infarction. With the exception of reperfusion therapy, attempts to salvage the myocardium during an acute myocardial infarction, showed disappointing results in directly decreasing infarct size. Nevertheless, the phenomenon of ischemic preconditioning (IPC) and ischemic postconditioning (IPO) results in a consistent and robust cardioprotective effect in every experimental animal model used. As a result, many studies have focused on the intracellular protective signaling pathways that are involved in preconditioning and postconditioning. More recently, it has been suggested that components of the reperfusion injury salvage kinases (RISK) pathway, protein kinase B (Akt) and the extra cellular signal regulated kinases (ERK1/2) can induce cardioprotection against I/R injury when they are activated during the post-ischemic reperfusion period. In addition, inhibition of mitochondrial permeability transistion (MPT) during post-ischemic reperfusion also showed a strong cardioprotective effect against I/R injury. The present mini-review highlights a short summary of the historical and present course of research into cardioprotection against myocardial I/R injury.