The endothelium forms a selective semi-permeable barrier controlling bidirectional transfer between blood vessel and irrigated tissues. This crucial function relies on the dynamic architecture of endothelial cell–cell junctions, and in particular, VE -cadherin-mediated contacts. VE -cadherin indeed chiefly organizes the opening and closing of the endothelial barrier, and is central in permeability changes. In this review, the way VE -cadherin-based contacts are formed and maintained is first presented, including molecular traits of its expression, partners, and signaling. In a second part, the mechanisms by which VE -cadherin adhesion can be disrupted, leading to cell–cell junction weakening and endothelial permeability increase, are described. Overall, the molecular basis for VE -cadherin control of the endothelial barrier function is of high interest for biomedical research, as vascular leakage is observed in many pathological conditions and human diseases.