The ubiquitin-proteasome system (UPS) has been recognized as a key regulatory pathway in cardiovascular diseases. Although the role of this system in the pathogenesis of endothelial dysfunction remains largely unknown, available data suggest that proteasome activity is modified by mediators and processes--e.g. nitric oxide and oxidative stress--involved in the regulation of endothelial function. In addition, there is some evidence that the UPS itself modulates the activity of endothelial nitric oxide synthase, the key enzyme of vascular homeostasis, interacts with other vasoactive mediators involved in regulation of endothelial function, influences oxidative stress response in the vasculature, and thereby contributes to regulation of endothelial (dys)function. This review discusses the potential implications of the UPS in endothelial dysfunction.