During post-natal maturation of the mammalian heart, proliferation of cardiomyocytes essentially ceases as cardiomyocytes withdraw from the cell cycle and develop blocks at the G0/G1 and G2/M transition phases of the cell cycle. As a result, the response of the myocardium to acute stress is limited to various forms of cardiomyocyte injury, which can be modified by preconditioning and reperfusion, whereas the response to chronic stress is dominated by cardiomyocyte hypertrophy and myocardial remodeling. Acute myocardial ischemia leads to injury and death of cardiomyocytes and nonmyocytic stromal cells by oncosis and apoptosis, and possibly by a hybrid form of cell death involving both pathways in the same ischemic cardiomyocytes. There is increasing evidence for a slow, ongoing turnover of cardiomyocytes in the normal heart involving death of cardiomyocytes and generation of new cardiomyocytes. This process appears to be accelerated and quantitatively increased as part of myocardial remodeling. Cardiomyocyte loss involves apoptosis, autophagy, and oncosis, which can occur simultaneously and involve different individual cardiomyocytes in the same heart undergoing remodeling. Mitotic figures in myocytic cells probably represent maturing progeny of stem cells in most cases. Mitosis of mature cardiomyocytes that have reentered the cell cycle appears to be a rare event. Thus, cardiomyocyte renewal likely is mediated primarily by endogenous cardiac stem cells and possibly by blood-born stem cells, but this biological phenomenon is limited in capacity. As a consequence, persistent stress leads to ongoing remodeling in which cardiomyocyte death exceeds cardiomyocyte renewal, resulting in progressive heart failure. Intense investigation currently is focused on cell-based therapies aimed at retarding cardiomyocyte death and promoting myocardial repair and possibly regeneration. Alteration of pathological remodeling holds promise for prevention and treatment of heart failure, which is currently a major cause of morbidity and mortality and a major public health problem. However, a deeper understanding of the fundamental biological processes is needed in order to make lasting advances in clinical therapeutics in the field.