Heart regeneration is a critical area of research due to the high mortality rate of heart failure, which affects millions of people globally. While lower vertebrates and developing mammals can regenerate heart tissue, human hearts have limited regenerative capacity after birth. This review discusses the barriers to heart regeneration in humans, evidence of cardiomyocyte turnover, and current experimental strategies using stem cells, cellular reprogramming, and tissue engineering to regenerate the injured heart. Heart regeneration has been studied for over 150 years, with extensive research on various species, including amphibians and zebrafish. Zebrafish hearts can fully regenerate after injury, with cardiomyocytes proliferating and preexisting cells contributing to the new tissue. In contrast, mammalian hearts show limited regeneration, with very low levels of cardiomyocyte proliferation. However, recent studies suggest that cardiomyocytes may be renewed in humans, though the process is slow and not well understood. Studies using genetic fate mapping in zebrafish and mice have shown that cardiomyocytes can regenerate from preexisting cells rather than from stem cells. In humans, evidence of cardiomyocyte turnover is limited, but some studies suggest that cardiomyocytes may be renewed, with estimates of turnover rates ranging from 1% to 45% per year. However, these findings are controversial, and the role of polyploidization in cardiomyocyte turnover remains unclear. Stem cell research has shown promise in cardiac repair, with pluripotent stem cells (ESCs and iPSCs) capable of generating cardiomyocytes. However, the clinical application of these cells is still in early stages, and challenges remain in terms of safety, efficiency, and scalability. Cardiac progenitor cells (CPCs) and bone marrow-derived cells have also been explored for their potential in cardiac repair, with some studies showing that these cells can contribute to myocardial regeneration. Tissue engineering has also been explored as a potential approach for cardiac repair, with the development of 3D scaffolds that can support the growth of cardiomyocytes and other cells. These scaffolds can be designed to promote vascularization and mechanical integration with the host tissue. However, the long-term success of these approaches is still under investigation. In conclusion, while heart regeneration in humans is limited, there is growing evidence that cardiomyocytes may be renewed, and various approaches, including stem cell therapy, cellular reprogramming, and tissue engineering, are being explored to enhance cardiac repair. Further research is needed to fully understand the mechanisms of heart regeneration and to develop effective therapeutic strategies for heart failure.Heart regeneration is a critical area of research due to the high mortality rate of heart failure, which affects millions of people globally. While lower vertebrates and developing mammals can regenerate heart tissue, human hearts have limited regenerative capacity after birth. This review discusses the barriers to heart regeneration in humans, evidence of cardiomyocyte turnover, and current experimental strategies using stem cells, cellular reprogramming, and tissue engineering to regenerate the injured heart. Heart regeneration has been studied for over 150 years, with extensive research on various species, including amphibians and zebrafish. Zebrafish hearts can fully regenerate after injury, with cardiomyocytes proliferating and preexisting cells contributing to the new tissue. In contrast, mammalian hearts show limited regeneration, with very low levels of cardiomyocyte proliferation. However, recent studies suggest that cardiomyocytes may be renewed in humans, though the process is slow and not well understood. Studies using genetic fate mapping in zebrafish and mice have shown that cardiomyocytes can regenerate from preexisting cells rather than from stem cells. In humans, evidence of cardiomyocyte turnover is limited, but some studies suggest that cardiomyocytes may be renewed, with estimates of turnover rates ranging from 1% to 45% per year. However, these findings are controversial, and the role of polyploidization in cardiomyocyte turnover remains unclear. Stem cell research has shown promise in cardiac repair, with pluripotent stem cells (ESCs and iPSCs) capable of generating cardiomyocytes. However, the clinical application of these cells is still in early stages, and challenges remain in terms of safety, efficiency, and scalability. Cardiac progenitor cells (CPCs) and bone marrow-derived cells have also been explored for their potential in cardiac repair, with some studies showing that these cells can contribute to myocardial regeneration. Tissue engineering has also been explored as a potential approach for cardiac repair, with the development of 3D scaffolds that can support the growth of cardiomyocytes and other cells. These scaffolds can be designed to promote vascularization and mechanical integration with the host tissue. However, the long-term success of these approaches is still under investigation. In conclusion, while heart regeneration in humans is limited, there is growing evidence that cardiomyocytes may be renewed, and various approaches, including stem cell therapy, cellular reprogramming, and tissue engineering, are being explored to enhance cardiac repair. Further research is needed to fully understand the mechanisms of heart regeneration and to develop effective therapeutic strategies for heart failure.