Mounting evidence suggests the regenerative potential of the mammalian heart. Nevertheless, the contribution of endogenous stem or precursor cells to adult cardiac regeneration upon myocardial injuries remains unclear. We hereby describe a genetic fate-mapping approach to study adult cardiomyocyte replenishment after myocardial injury. Using double transgenic MerCreMer-ZEG mice, the fate of adult cardiomyocytes can be tracked by the expression of green fluorescence protein (GFP) specifically induced in cardiomyocytes. Upon experimental myocardial infarction, a reduction in GFP expression in the myocardium is observed, indicating the refreshment of cardiomyocytes by endogenous stem or precursor cells.