In spite of remarkable progress in medical and surgical therapy for heart disease, congestive heart failure (CHF) and coronary artery disease (CAD) are major causes of morbidity and mortality in the US. Although implantation of a left ventricular assist device has recently emerged as a promising therapy for CHF, no other therapy holds as much promise for the treatment of patients suffering from cardiovascular disease other than cardiac regeneration. In this regard, there are substantial pre-clinical and clinical studies that have elucidated the safety and efficacy of cardiac stem cell-based therapy using a variety of cell lines to promote regeneration of the heart. In spite of promising results in both animal and human studies, the exact fate of these administered stem cells within the human heart is poorly understood as is the mechanism by which they promote myocardial recovery and regeneration. These limitations of our current knowledge base can be considered a critical issue limiting widespread application of stem cell-based therapy.