The placental labyrinth – a complex structure made up of trophoblasts and endothelial cells – provides the interface for gas and nutrient exchange between the embryo and the mother and hence is essential for embryogenesis. However, the molecular mechanisms that underlie the development of this vital labyrinth, particularly those that influence its vascularization, are poorly understood. Here, on p. 2392, Yoshiaki Kubota, Satoru Yamagishi and co-workers report the unexpected finding that fibronectin leucine-rich transmembrane protein 2 (FLRT2), which is a protein that acts as a chemorepellent in neurons, regulates placental labyrinth development in mice. They report that FLRT2 is expressed in endothelial cells specifically in the placental labyrinth. The researchers further demonstrate that the vasculature is poorly formed and aberrantly organized in FLRT2-deficient placentas, with FLRT2-deficient embryos exhibiting high levels of hypoxia. In vitro assays reveal that, as occurs in neurons, FLRT2 signals through UNC5B and can mediate cell repulsion. Following on from this, the authors show that Unc5b deletion recapitulates the vascular defects observed in Flrt2-deficient placentas. Together these exciting results point towards a role for inter-endothelial repulsion, mediated by FLRT2, during placental morphogenesis.