Recent evidence would suggest that the heart is not a terminally differentiated organ and has the ability to regenerate itself under normal and pathophysiologic conditions. A major effort has been made to identify precursor cells that are capable of differentiating into cell lineages different from their organ of origin. Embryonic stem cells and bone marrow-derived cells (BMCs) have been studied and characterized, and BM precursor cells are currently being utilized as therapy in clinical trials of patients with heart failure of ischemic and nonischemic etiologies. Controversy remains, however, whether BMCs are the best cells to be used for replacement therapy. The existence of a cardiac stem cell (CSC) has also been described, which has the ability to generate new cardiac myocytes and blood vessels, raising the possibility of rebuilding a damaged heart with the organ's own precursor stem cell population. Animal studies have suggested such a possibility, and a clinical trial using CSCs is in progress. This monograph discusses our current understanding of myocardial regeneration and the roles that endogenous and exogenous stem cells may have in the future therapy of cardiovascular disease.