Many forms of cardiovascular disease are associated with cardiomyocyte loss via necrosis and/or apoptosis. The cumulative loss of contractile cells ultimately results in diminished cardiac function. Numerous approaches have been employed to reduce the rate of cardiomyocyte loss, or alternatively, to repopulate the heart with new cardiomyocytes. Strategies aimed at repopulating the heart include cardiomyocyte cell therapy, myogenic stem cell therapy, and cell cycle activation therapy. All three approaches are based on the assumption that the de novo cardiomyocytes will participate in a functional syncytium with the surviving myocardium. This review will discuss the current status of interventions aimed at repopulating the heart with functional cardiomyocytes.