Vascular endothelial (VE)-cadherin is a strictly endothelial specific adhesion molecule located at junctions between endothelial cells. In analogy of the role of E-cadherin as major determinant for epithelial cell contact integrity, VE-cadherin is of vital importance for the maintenance and control of endothelial cell contacts. Mechanisms that regulate VE-cadherin–mediated adhesion are important for the control of vascular permeability and leukocyte extravasation. In addition to its adhesive functions, VE-cadherin regulates various cellular processes such as cell proliferation and apoptosis and modulates vascular endothelial growth factor receptor functions. Consequently, VE-cadherin is essential during embryonic angiogenesis. This review will focus on recent new developments in understanding the role of VE-cadherin in controlling endothelial cell contacts and influencing endothelial cell behavior by various outside-in signaling processes.