Cardiovascular diseases remain the leading cause of death worldwide, and the burden is equally shared between men and women around the globe. Cardiomyocytes that die in response to disease processes or aging are replaced by scar tissue instead of new muscle cells. Although recent reports suggest an intrinsic capacity for the mammalian myocardium to regenerate via endogenous stem/progenitor cells, the magnitude of such a response appears to be minimal and has yet to be realized fully in cardiovascular patients. Despite the advances in pharmacotherapy and new biomedical technologies, the prognosis for patients diagnosed with end-stage heart failure appears to be grave. While heart transplantation is a viable option, this life-saving intervention suffers from an acute shortage of cardiac organ donors. In view of these existing issues, donor cell transplantation is emerging as a promising strategy to regenerate diseased myocardium. Studies from multiple laboratories have shown that transplantation of donor cells (e.g. fetal cardiomyocytes, skeletal myoblasts, smooth muscle cells, and adult stem cells) can improve the function of diseased hearts over a short period of time (1-4 weeks). While long-term follow-up studies are warranted, it is generally perceived that the beneficial effects of transplanted cells are mainly due to increased angiogenesis or favorable scar remodeling in the engrafted myocardium. Although skeletal myoblasts and bone marrow stem cells hold the highest potential for implementation of autologous therapies, initial results from phase I trials are not promising. In contrast, transplantation of fetal cardiomyocytes has been shown to confer protection against the induction of ventricular tachycardia in experimental myocardial injury models. Furthermore, results from multiple laboratories suggest that fetal cardiomyocytes can couple functionally with host myocytes, stimulate formation of new blood vessels, and improve myocardial function. While it is neither practical nor ethical to test the potential of fetal cardiomyocytes in clinical trials, embryonic stem (ES) cells serve as a novel source for generation of unlimited quantities of cardiomyocytes for myocardial repair. The initial success in the application of ES cells to partially repair and improve myocardial function in experimental models of heart disease has been quite promising. However, multiple hurdles need to be crossed before the potential benefits of ES cells can be translated to the clinic. In this review, we summarize the current knowledge of cardiomyocyte derivation and enrichment from ES-cell cultures and provide a brief survey of factors increasing cardiomyogenic induction in both mouse and human ES cultures. Subsequently, we summarize the current state of research using mouse and human ES cells for the treatment of heart disease in various experimental models. Furthermore, we discuss the challenges that need to be overcome prior to the successful clinical utilization of ES-derived cardiomyocytes for the treatment of end-stage heart disease. While we are optimistic that the researchers in this field will sail across the hurdles, we also suggest that a more cautious approach to the validation of ES cardiomyocytes in experimental models would certainly prevent future disappointments, as seen with skeletal myoblast studies.