Congestive heart failure and coronary artery disease are the leading causes of morbidity and mortality in the western society despite substantial therapeutic advances in the last half century. Only very recently have studies arisen that support possibility of regenerating tissue of damaged human organs including the heart. In this regard, there is growing preclinical and clinical evidence demonstrating the safety and efficacy of cell-based myocardial regeneration using a variety of cell lines. Different mechanisms have been proposed to explain the beneficial effects of cell-based therapy. The beneficial effects of cell therapy may involve multiple mechanisms. The encouraging results of early clinical cell therapy studies have not been sustained by subsequent robust studies for all cell types. These findings suggest that many unanswered questions need to be addressed before cell therapy becomes an acceptable adjunctive treatment for heart disease. Future setbacks are likely, but both clinicians and basic scientists will eventually introduce more potent cell-based strategies into the clinical arena.