The adult mammalian heart was long thought to be a nonregenerating organ; however, recent evidence suggests otherwise. After many studies, a consensus has emerged that low levels of cardiomyocyte turnover occurs in the adult mammalian heart, originating primarily from preexisting cardiomyocytes with negligible contributions from any type of stem cell population. In this chapter, we highlight the critical studies that helped arrive at this conclusion We also discuss innovative approaches and potential therapeutic strategies that can generate new functional cardiac muscle tissue in the postnatal mammalian heart.