Myocardial protection and specifically cardioplegia have been extensively investigated in the beginnings of cardiac surgery. After cardiopulmonary bypass had become routine, more and more cardiac operations were possible, requiring reliable and reproducible protection for times of blood flow interruptions to the most energy-demanding organ of the body. The concepts of hypothermia and cardioplegia evolved as tools to extend cardiac ischaemia tolerance to a degree considered safe for the required operation. A plethora of different solutions and delivery techniques were developed achieving remarkable outcomes with cross-clamp times of up to 120 min and more. With the beginning of the new millennium, interest in myocardial protection research declined and, as a consequence, conventional cardiac surgery is currently performed using myocardial protection strategies that have not changed in decades. However, the context, in which cardiac surgery is currently performed, has changed during this time. Patients are now older and suffer from more comorbidities and, thus, other organs move more and more into the centre of risk assessment. Yet, systemic effects of cardioplegic solutions have never been in the focus of attention. They say hindsight is always 20–20. We therefore review the biochemical principles of ischaemia, reperfusion and cardioplegic extension of ischaemia tolerance and address the concepts of myocardial protection with ‘hindsight from the 2020s’. In light of rising patient risk profiles, minimizing surgical trauma and improving perioperative morbidity management becomes key today. For cardioplegia, this means accounting not only for cardiac, but also for systemic effects of cardioplegic solutions.