The clinical outcomes for heart failure remain poor because current therapies do not address a critical feature of heart failure – loss of functional cardiomyocytes. To decrease the morbidity and mortality of patients with heart failure, multiple strategies are being developed to replace dead cardiomyocytes with new, functional ones. Adult stem cell transplantation studies have had modest clinical benefits primarily attributed to paracrine effects on several endogenous processes including cardiac regeneration. Many cardiac progenitor cell populations have been isolated from the adult mammalian heart and studied in cell culture or after transplantation; however, their roles in endogenous cardiac regeneration are highly contested. In the thesis work presented here, we used the side population phenotype as an unbiased approach to determine whether an endogenous progenitor cell population exists in the adult mammalian heart. We generated a new Abcg2-driven, lineage-tracing mouse model that efficiently labels side population cells in multiple tissues throughout the body, including the heart. With this mouse model, we first showed that the side population phenotype enriches for endogenous stem cells in the bone marrow and small intestine under homeostatic conditions. In the adult heart, we showed that cardiac side population cells contribute to 21% of newly formed cardiomyocytes either through direct differentiation or fusion. Moreover, cardiac side population cells are responsive to different forms of cardiac injury. Further characterization of cardiac side population cells will help us understand how they can be targeted in vivo for the development of new heart failure therapies.