The adult mammalian heart, including humans, harbors bone fide cardiac stem cells (CSCs) distributed throughout the atria and ventricles. Their discovery almost four years ago initiated a brand new field of cardiac regenerative biology that has profoundly changed the outlook of developmental and adult cardiac biology/physiology and the potential for treating cardiac failure. Indeed, despite its initial hesitance, the research community has now accepted that the heart has an endogenous myocardial regenerative potential owed to CSCs, which challenges the previous accepted notion of the adult heart as a post-mitotic organ. Also, burgeoning evidence is converging to the possibility that CSCs are actually the founder of the heart in the embryonic life. CSCs are involved in cardiac cellular homeostasis during aging and adaptation to physiological and pathological stress. When transplanted into damaged hearts, CSCs have the capacity to generate significant new myocardial tissue and ameliorate ventricular function. However, more relevant for translational research and its application for future regeneration protocols, this reservoir of CSCs can also be activated by local injections of several growth factors or through the administration of systemic drugs, such as statins, to obtain beneficial results similar to those of CSC transplantation. The present review highlights current knowledge on the biology of CSCs and the prospects of CSC activation in situ, without the need for cell expansion in vitro and consequent transplantation.