Tetraspanins are multiple membrane-spanning proteins that likely function as the organizers of membrane microdomains. Tetraspanins associate with other membrane-bound molecules such as cell-adhesion proteins, growth factor receptors, and Ig superfamily members and regulate key cellular processes such as adhesion, migration, and fusion. Tetraspanins are widely expressed in vascular and haematopoietic cells and are involved in both physiological and pathological processes related to angiogenesis, vascular injury, thrombosis, and haemostasis. A wide body of evidence suggests that tetraspanins directly regulate the development and functions of the vascular system and the pathogenesis of vascular diseases. This article reviews current understanding of the roles of tetraspanins in vascular functions.