Over the last 20 years, an increasing number of patients with multimorbidity and polypharmacy underwent different types of elective non-cardiac and cardiac surgery. Despite surgery is safer today than in the past, rate of perioperative major adverse cardiovascular events is still attracting significant attention from both clinicians and researchers. The perioperative myocardial infarction (PMI), a permanent damage of the heart, is a major cause of short- and long-term morbidity and mortality in current surgical populations. Although it is primarily the result of local myocardial ischemia during major noncardiac surgery, high-risk patients undergoing cardiac surgery are also susceptible to PMI following an acute global ischemia/reperfusion injury. Since recent large-scale randomized controlled trials revealed the poor perioperative effectiveness of some available medications, it is conceivable that deeper clarification of adaptive response pathways of cardiac cells to perioperative myocardial injury would be appropriate to develop approaches that enhance cardioprotection in both surgery types. Indeed, solid preclinical data have highlighted the role of non-myocyte cells in promoting earlier cardiomyocytes survival in an epigenetic manner. These findings challenge our view of what may be feasible in terms of perioperative cardioprotection, despite technological limitations. Here, we will first analyze recent large-scale trials regarding current cardioprotective aids in non-cardiac and cardiac surgery. Finally, we will review novel cardioprotective targets translatable to surgical patients.