Cardiac regenerative medicine is evolving towards more organic approaches that are increasingly aligned with our evolutionary biology. This is a much-needed direction given the tumultuous path this field has seen over the last two decades. Limited regenerative potential of the adult mammalian heart is indisputably a major factor contributing to the extensive morbidity and mortality of cardiovascular disease worldwide. Many studies are underway globally in the pursuit of this ‘holy grail’ of cardiovascular medicine, i.e., strategies to actually repopulate lost cardiomyocytes after myocardial infarction or in the setting of heart failure. A multitude of stem cell types have been tested for cardiac repair with clinical trials in this arena falling short of bona fide regeneration, yet more clinical testing of presumed multipotent stem cells is likely to continue. Growth factors, reprogramming and exosomes are also being examined; yet pre-clinical studies have only been reported for growth factor therapy. Cell cycle regulation of cardiomyocyte proliferation is an area our laboratory was amongst the first to report and this is receiving much greater attention recently in light of marginal results noted in past clinical stem cell trials. Gene and cell-based approaches should carefully leverage underpinnings from developmental pathways, which then progress to preclinical studies in large animal models that mimic human cardiac anatomy and physiology prior to the transition to clinical trials.