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A few decades ago, cardiac muscle was discovered to possess signalling pathways that, when activated, protect the myocardium against the damage induced by ischaemia-reperfusion. The ability of cardiac muscle to protect itself against injury has been termed ‘cardioprotection’. Many compounds and procedures can trigger cardioprotection including conditionings (exposure to brief episodes of ischaemia-reperfusion to protect against sustained ischaemia-reperfusion), hypoxia, adenosine, acetylcholine, adrenomedullin, angiotensin, bradykinin, catecholamines, endothelin, estrogens, phenylephrine, opioids, testosterone, and many more. These triggers activate many intracellular signalling factors including protein kinases, different enzymes, transcription factors and defined signalling pathways to target structures in mitochondria, sarcoplasmic reticulum, nucleus and sarcolemma to mediate cardioprotection. Although a lot of information about cardioprotection has been acquired, there are still two major outstanding issues to be addressed in the future 1) better understanding of spatio-temporal relationships between signalling elements, and; 2) devising therapeutic strategies against myocardial diseases based on cardioprotective signalling. Further research is required to paint integral picture of cardioprotective signalling and more clinical studies are required to properly test clinical efficacy and safety of potential cardioprotective strategies. Therapies against cardiac diseases based on cardioprotective strategies would be a perfect adjunct to current therapeutic strategies based on restitution of coronary blood flow and regulation of myocardial metabolic demands.