The adult mammalian myocardium has a robust intrinsic regenerative capacity because of the presence of cardiac stem cells (CSCs). Despite being mainly composed of terminally differentiated myocytes that cannot re-enter the cell cycle, the heart is not a postmitotic organ and maintains some capacity to form new parenchymal cells during the lifespan of the organism. Myocyte death and formation of new myocytes by the CSCs are the two processes that enable this organ to maintain a proper and uninterrupted cardiac output from birth to adulthood and into old age. CSCs are activated in response to pathological or physiological stimuli, whereby they enter the cell cycle and differentiate into new myocytes (and vessels) that significantly contribute to changes in myocardial mass. The future of regenerative cardiovascular medicine is arguably dependent on our success in dissecting the biology and mechanisms regulating the number, growth, differentiation, and aging of CSCs. This information will generate the means to manipulate CSC growth, survival, and differentiation and, therefore, will provide the tools for the design of more physiologically relevant clinical regeneration protocols. In this article, we review the developments in cardiac cell biology that might, in our opinion, have a broad impact on cardiovascular medicine.