Cardiac repair is a dream in the field of medical science. The biological limitations to human cardiac regenerative growth require the creation of new strategies for cardiac regeneration using cells, genes and protein. Recent experimental studies and early-phase clinical trials showed stem cells have the potential to enhance myocardial perfusion and contractile performance in patients with acute myocardial infarction, advanced coronary artery disease and chronic heart failure. Overall clinical experience also suggests that stem cell therapy can be safely performed if the right cell protocol is used within the correct clinical setting. Some experimental data have shown stable stem cell engraftment due to fusion or transdifferentiation into cardiomyocyte or vascular cell lineages, which could be likely explanations for these beneficial effects. Others have proposed that transient cell retention may be sufficient to promote functional effects, e.g., by release of paracrine mediators. We should proceed cautiously with carefully designed clinical trials, and concern for patient safety must remain the key issue. The translational basic research will be required to elucidate the mechanism of stem cell therapy.