During placental formation, trophoblasts invade and remodel uterine vessels in order to re-route maternal blood to the placenta to nourish the developing embryo. This process fails in pre-eclampsia, a serious but common pregnancy complication. Here (see p. 2987), Susan Fisher and colleagues report that Notch signalling plays a key role in trophoblast endovascular invasion. By immunostaining human placental tissue sections, the researchers show that Notch receptors/ligands are modulated in a stepwise manner during trophoblast invasion. Inhibition of Notch signalling reduces invasion of cultured human trophoblasts and expression of the arterial marker EFNB2. Similarly, in mice, conditional deletion of Notch2 reduces arterial invasion, the size of maternal blood canals and placental perfusion, and leads to litter-wide lethality. Finally, in placental tissue sections obtained from women with pre-eclampsia, expression of the Notch ligand JAG1 is absent in perivascular and endovascular trophoblasts. Together, these results indicate that Notch signalling is crucial for trophoblast vascular invasion and that Notch signalling defects are involved in the pathogenesis of pre-eclampsia.