A study published in *Nature* (2013) investigates the origin of new cardiomyocytes in adult mammals. The research combines genetic fate-mapping with stable isotope labeling and Multi-isotope Imaging Mass Spectrometry (MIMS) to track cardiomyocyte turnover. The findings reveal that cardiomyocytes in adult mammals primarily arise from the division of pre-existing cardiomyocytes, rather than from stem cells or progenitors. During normal aging, cardiomyocyte renewal occurs at a low rate, but this rate increases significantly near areas of myocardial injury. The study shows that cardiomyocytes undergo DNA synthesis without completing the cell cycle, leading to polyploidy and multinucleation. However, a significant fraction of new cardiomyocytes are diploid and mononucleated, indicating division of pre-existing cells. In the context of myocardial injury, the rate of cardiomyocyte division increases, with new cardiomyocytes arising from pre-existing cells. These findings suggest that pre-existing cardiomyocytes are the dominant source of cardiomyocyte replacement in both normal myocardial homeostasis and after injury. The study also addresses the debate over the role of stem cells in cardiac regeneration. While some studies suggest a high rate of stem cell activity, others indicate that new cardiomyocytes are generated mainly from pre-existing cells. The use of MIMS and genetic fate-mapping techniques allows for precise tracking of cardiomyocyte turnover, revealing that stem cells do not play a significant role in myocardial homeostasis or regeneration after injury. The results support the idea that the adult mammalian heart has limited regenerative capacity, with cardiomyocyte renewal primarily occurring through the division of pre-existing cells. The study highlights the importance of understanding the mechanisms of cardiomyocyte renewal for developing therapeutic strategies in heart disease.A study published in *Nature* (2013) investigates the origin of new cardiomyocytes in adult mammals. The research combines genetic fate-mapping with stable isotope labeling and Multi-isotope Imaging Mass Spectrometry (MIMS) to track cardiomyocyte turnover. The findings reveal that cardiomyocytes in adult mammals primarily arise from the division of pre-existing cardiomyocytes, rather than from stem cells or progenitors. During normal aging, cardiomyocyte renewal occurs at a low rate, but this rate increases significantly near areas of myocardial injury. The study shows that cardiomyocytes undergo DNA synthesis without completing the cell cycle, leading to polyploidy and multinucleation. However, a significant fraction of new cardiomyocytes are diploid and mononucleated, indicating division of pre-existing cells. In the context of myocardial injury, the rate of cardiomyocyte division increases, with new cardiomyocytes arising from pre-existing cells. These findings suggest that pre-existing cardiomyocytes are the dominant source of cardiomyocyte replacement in both normal myocardial homeostasis and after injury. The study also addresses the debate over the role of stem cells in cardiac regeneration. While some studies suggest a high rate of stem cell activity, others indicate that new cardiomyocytes are generated mainly from pre-existing cells. The use of MIMS and genetic fate-mapping techniques allows for precise tracking of cardiomyocyte turnover, revealing that stem cells do not play a significant role in myocardial homeostasis or regeneration after injury. The results support the idea that the adult mammalian heart has limited regenerative capacity, with cardiomyocyte renewal primarily occurring through the division of pre-existing cells. The study highlights the importance of understanding the mechanisms of cardiomyocyte renewal for developing therapeutic strategies in heart disease.