VE-cadherin is a component of endothelial cell-to-cell adherens junctions, and it has a key role in the maintenance of vascular integrity. During embryo development, VE-cadherin is required for the organization of a stable vascular system, and in the adult it controls vascular permeability and inhibits unrestrained vascular growth. The mechanisms of action of VE-cadherin are complex and include reshaping and organization of the endothelial cell cytoskeleton and modulation of gene transcription. Here we review some of the most important pathways through which VE-cadherin modulates vascular homeostasis and discuss the emerging concepts in the overall biological role of this protein.