Cardiomyocyte proliferation gradually declines during embryogenesis resulting in severely limited regenerative capacities in the adult heart. Understanding the developmental processes controlling cardiomyocyte proliferation may thus identify new therapeutic targets to modulate the cell cycle activity of cardiomyocytes in the adult heart. In the present study, we investigate the mechanism by which FGF10 controls fetal cardiomyocyte proliferation and test the hypothesis that FGF10 promotes the proliferative capacity of adult cardiomyocytes. Analysis of Fgf10-/- hearts and primary cardiomyocyte cultures reveals that altered ventricular morphology is associated with impaired proliferation of right ventricular myocytes. Decreased FOXO3 phosphorylation associated with upregulated p27kip1 levels were observed specifically in the right ventricle of Fgf10-/- hearts. In addition, cell type specific expression analysis revealed that Fgf10 and its receptor, Fgfr2b, are predominantly expressed in cardiomyocytes rather than cardiac fibroblasts, consistent with a cell-type autonomous role of FGF10 in regulating regional specific myocyte proliferation in the fetal heart. Furthermore, we demonstrate that in vivo overexpression of Fgf10 in adult mice results in an upregulation of cardiomyocyte but not cardiac fibroblast proliferation. In conclusion, this study identifies FGF10 as a regulator of regional cardiomyocyte-autonomous proliferation in the fetal heart through a FOXO3/p27kip1 pathway. In addition, FGF10 triggers cell cycle reentry of adult cardiomyocytes and is thus a potential target for cardiac repair.