<p>Organs vary in size between and within species to match organismal needs. Theoretical work has proposed that scaling of organs and body parts relies on energy-transport systems, the vascular system in mammals. Here, we use quantitative clonal mapping and volumetric imaging combined with novel molecular and genetic tools to identify temporal and spatial constraints that establish mouse liver size. We find that adult liver size is foreshadowed during a neonatal period when functional units, termed lobules, initiate growth. Nascent lobules are vascularized by prominent sprouting angiogenesis of the hepatic vein, restricted to the periphery of the organ. When Wnt signals are ablated in the single cell-layered mesothelium at the periphery, neonatal growth is disturbed, and the liver adopts a compromised size set point. Similarly, when venous angiogenesis is inhibited, nascent lobules remain small and the liver fails to reach proper size. In unperturbed animals, vein sprouting rapidly declines within a week after birth and well before hepatocyte division stops. These findings suggest that vascularization in the neonate assists in the determination of adult liver size. Together, these results lead us to propose a vasculature-centric experimental framework for studying organ size control and scaling in mammals.</p>