Vascular development and maintenance of proper vascular function through various regulatory mechanisms are critical to our wellbeing. Delineation of the regulatory processes involved in development of the vascular system and its function is one of the most important topics in human physiology and pathophysiology. Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), a cell adhesion molecule with proangiogenic and proinflammatory activity, has been the subject of numerous studies. In the present review, we look at the important roles that PECAM-1 and its isoforms play during angiogenesis, and its molecular mechanisms of action in the endothelium. In the endothelium, PECAM-1 not only plays a role as an adhesion molecule but also participates in intracellular signalling pathways which have an impact on various cell adhesive mechanisms and endothelial nitric oxide synthase (eNOS) expression and activity. In addition, recent studies from our laboratory have revealed an important relationship between PECAM-1 and endoglin expression. Endoglin is an essential molecule during angiogenesis, vascular development and integrity, and its expression and activity are compromised in the absence of PECAM-1. In the present review we discuss the roles that PECAM-1 isoforms may play in modulation of endothelial cell adhesive mechanisms, eNOS and endoglin expression and activity, and angiogenesis.