Heart failure is a devastating disease with mortality rates exceeding many malignancies. The pathophysiological basis of systolic heart failure lies in the inability of the adult mammalian heart to regenerate lost or damaged myocardium. Although limited cardiomyocyte turnover does in fact occur in the adult mammalian heart, it is insufficient for restoration of contractile function following injury. In contrast to the adult mammalian heart, my group has shown that newborn mammals have a remarkable endogenous myocardial regenerative capacity, mediated by proliferation of preexisting cardiomyocytes. Nevertheless, the mere realization that the heart is not a post-mitotic organ created a lot of excitement in the past two decades and led to a flurry of bench and clinical studies aimed at outlining the cardiac regenerative potential of various cell types. While many of these studies may hold therapeutic promise, mounting evidence suggest that cell therapy may enhance some endogenous repair or regenerative mechanisms such as stimulation of cardiomyocyte proliferation. Importantly, current evidence suggests that both the regenerative ability of the early postnatal heart, and cardiomyocyte turnover in the adult heart are mediated by proliferative competency of pre-existing cardiomyocytes. However, mechanisms of regulation of mammalian cardiomyocyte cell cycle arrest shortly after birth remain poorly understood. Therefore, we believe that a program focused on understanding mechanisms of cardiomyocyte cell cycle regulation could inform future therapeutic interventions for heart regeneration. Our studies are focused on three broad questions: 1) Is loss of the regenerative capacity of the mammalian myocardium an evolutionary tradeoff to gain metabolic efficiency? 2) How is the slow turnover of cardiomyocytes in the adult heart regulated? 3) Does cardiac mechanical load represent a regenerative block