Human placental development is characterised by the preferential remodelling of uterine arterioles by fetal cytotrophoblast cells. Now Red-Horse and colleagues provide a molecular explanation for this preference(see p. 4097). These researchers found that when cytotrophoblasts commit to uterine invasion, they rapidly downregulate the ephrin receptor EPHB4, which is associated with venous identity, and upregulate the ligand ephrin B1. In vitro,cytotrophoblasts avoid EPHB4-coated substrates and dramatically decrease their migration when co-cultured with cells expressing this receptor. Once in the uterine wall, cytotrophoblasts upregulate ephrin B2 expression, a mark of arterial identity. From these findings, the authors propose that EPHB4/ephrin B1 interactions generate repulsive signals that direct cytotrophoblast invasion towards the uterus, where chemokines stimulate their migration through the endometrium. When cytotrophoblasts encounter EPH4B-expressing venous epithelium, ephrin B-generated repulsive signals and reduced chemokine-mediated responses limit their interaction with veins. These findings highlight a possible role for ephrin signalling in the initiation and maintenance of human pregnancies.