The limited potential of the adult mammalian heart to regenerate itself has been a longstanding challenge in the field of cardiovascular biology. The cell cycle exit of adult cardiomyocytes and the lack of endogenous stem cells that can differentiate into cardiomyocytes after injury forms the basis for these limitations. Despite a myriad of cell types investigated in clinical trials, moving cell therapy from bench to bedside has been disappointing in terms of genuine cardiomyocyte generation and functional improvement. Studies in animals lacked scientific rigor in terms of assessing the true cardiomyogenic potential of stem cells and created a void in ongoing research in this direction. This warrants critical assessment of cell types used and further emphasizes the need for large animal experiments prior to their translation to clinic. Here we address the current understanding of cell-based and cell-free approaches thus far and delineate the prerequisites of regenerative therapies for successful preclinical and clinical studies. Our own understanding involving placental stem cells and gene therapy approaches using cell cycle regulators suggest that strategies that leverage developmental underpinnings likely represent the most potent treatment approaches aimed at cardiac regeneration. As such, investigations into both gene and cell therapy approaches should work in concert to develop successful strategies to regenerate the injured heart.