Treatment of patients with heart failure secondary to myocardial infarction remains a therapeutic challenge. Extensive myocyte death in the heart and post-ischemic remodeling accentuate progressive expansion of the scar area and compromise left ventricular contractile function. The scarcity of resident stem cells in the heart and limited proliferative capacity of adult cardiomyocytes warrant novel strategies of outside intervention to supplement the inept intrinsic repair mechanism. Heart cell therapy using patient's own skeletal muscle derived myoblasts (SkMs) provides a relatively simple and inexpensive therapeutic option. Phase-I and II clinical trials supported by plethora of pre-clinical studies have shown the safety and effectiveness of SkM engraftment in the treatment of infarcted heart. However, before widespread application of this approach in the clinical settings, there remain some fundamental issues including extensive donor cell death during acute phase after SkMs engraftment, failure of SkMs to adopt cardiac phenotype and transient ventricular arrhythmias subsequent to SkMs transplantation which require serious considerations. This review will provide profound analysis of merits and limitations of SkMs as the choice cells for heart cell therapy and will summarize the potential of genetic and pharmacological manipulation SkMs to enhance their therapeutic efficacy for myocardial repair.