Repair of the heart is an old dream of physicians caring for patients with cardiac disease. Experimental studies suggest that cardiac transfer of stem and progenitor cells can have a favorable impact on tissue perfusion and contractile performance of the injured heart. Some researchers favor stable stem cell engraftment by fusion or transdifferentiation into cardiomyocyte or vascular cell lineages as likely explanations for these beneficial effects. Others have proposed that transient cell retention may be sufficient to promote functional effects, eg, by release of paracrine mediators. Although the mechanistic underpinnings of stem cell therapy are still intensely debated, the concept of cell therapy has already been introduced into the clinical setting, where a flurry of small, mostly uncontrolled trials indicate that stem cell therapy may be feasible in patients. The overall clinical experience also suggests that stem cell therapy can be safely performed, if the right cell type is used in the right clinical setting. Preliminary efficacy data indicate that stem cells have the potential to enhance myocardial perfusion and/or contractile performance in patients with acute myocardial infarction, advanced coronary artery disease, and chronic heart failure. The field now is rapidly moving toward intermediate-size, double-blinded trials to gather more safety and efficacy data. Ultimately, large outcome trials will have to be conducted. We need to proceed cautiously with carefully designed clinical trials and keep in mind that patient safety must remain the key concern. At the same time, continued basic research to elucidate the underlying mechanism of stem cell therapy is clearly needed.