The idea of protecting the heart from ischemic insult during heart surgery to allow elective cardiac arrest is as old as the idea of cardiac surgery itself. The current gold standard in clinical routine is a high potassium regimen added either to crystalloid or blood cardioplegic solutions inducing depolarized arrest. Ongoing patient demographic changes with increasingly older, comorbidly ill patients and increasing case complexity with increasingly structurally abnormal hearts as morphological correlate paired with evolutions in pediatric cardiac surgery allowing more complex procedures than ever before redefine requirements for cardioprotection. Many, in part adversarial, regimens to protect the myocardium from ischemic insults have entered clinical routine; however, functional recovery of the heart is still often impaired due to perfusion injury. Myocardial reperfusion damage is a key determinant of postoperative organ functional recovery, morbidity, and mortality in adult and pediatric patients. There is a discrepancy between what current protective strategies are capable of and what they are expected to do in a rapidly changing cardiac surgery community. An increased understanding of the molecular players of ischemia reperfusion injury offers potential seeds for new cardioprotective regimens and may further displace boundaries of what is technically feasible.