Every year, almost 1 million people in the United States suffer a myocardial infarction, and those who survive are likely to join the nearly 5.3 million people living with congestive heart failure [1]. The irreplaceable loss of cardiomyocytes during infarction creates an electromechanically dysfunctional tissue substrate that is incapable of supporting a healthy body and prone to life-threatening arrhythmias. Although recent studies have proved that the heart has endogenous repair mechanisms, including the recruitment and maturation of resident stem cells [2], the natural regenerative ability of cardiac tissue is apparently insufficient to prevent the occurrence of heart failure [3], [4]. Therefore, the transplantation of exogenous cells into the damaged myocardium (cellular cardiomyoplasty) has been actively pursued as a method to improve compromised heart function.A large number of animal studies and recent clinical trials have shown that the implantation of adult stem cells (including myoblasts [5], bone marrow [6], mesenchymal or marrow stromal [7], and resident cardiac stem cells [8]) as well as embryonic stem cells [9] into the infarcted heart can yield significant functional benefits. However, obstacles inherent to the multipotent and proliferative nature of stem cells and the potential risks associated with the application of exogenous cells into the heart may reduce the translational potential of this research. The use of genetic engineering to induce or alter specific protein expression in stem cells has already facilitated research in this field and may, additionally, offer a potential route for designing more efficient cell sources for cardiac repair. As the feasibility of stem cell genetic manipulation has already been proved and as genetic techniques continue to advance [10]-[13], the combinatorial approach for cardiac cell therapy is promising. This review will thus describe the applications of genetic engineering to improve the isolation, selection, and differentiation of stem cells prior to implantation as well as strategies to promote the retention, mobilization, survival, integration, and tracking of stem cells after implantation.