Maturation of a vascular plexus is a critical and yet incompletely understood process in organ development, and known maturation factors act universally in all vascular beds. In this study, we show that CXCL12 is an organ-specific maturation factor of particular relevance in coronary arterial vasculature. In vitro, CXCL12 does not influence nascent vessel formation, but promotes higher-order complexity of preinitiated vessels. In the heart, CXCL12 is expressed principally by the epicardium, and its receptor CXCR4 is expressed by coronary endothelial cells. CXCL12 is not a chemotactic signal for endothelial cell migration, but rather acts in a paracrine manner to influence the maturation of the coronary vascular plexus. Mutants in CXCL12 signaling show an excess of immature capillary chains and a selective failure in arterial maturation, and become leaky with the onset of coronary perfusion. Failed maturation of the coronary system explains the late-gestation lethality of these mutants.