It is estimated that a typical myocardial infarction results in the loss of approximately one billion functional cardiomyocytes, which are replaced by a non-contractile fibrous scar, eventually leading to heart failure. The currently available surgical, drug, and device-based therapies cannot reverse the loss of functional myocardium, which is the fundamental cause of the problem. As a result of this lack of an available medical solution, heart failure has evolved into a global epidemic. Therefore, the development of regenerative therapeutic strategies to halt the progression of ischemic heart disease to advanced heart failure has become one of the most urgent medical needs of this century. This review first addresses the extremely limited endogenous regenerative capacity of the mammalian heart, and the benefits and limitations of stem cell-based therapies for cardiac repair. Then it discusses the known roles of microRNAs after cardiac injury and the possibility of employing microRNAs to enhance cardiac regeneration.