Metabolic disorders such as obesity are accompanied by endothelial cell (EC) dysfunction and decreased vascular density. The current paradigm posits that metabolic alterations associated with obesity secondarily lead to EC dysfunction. However, in view of recent evidence reporting that EC dysfunction per se is able to cause metabolic dysregulation, this paradigm should be revisited and further elaborated. In this article we summarize current views and discuss evidence in favor of a causal role for ECs in systemic metabolic dysregulation. We also integrate and contextualize current research in a pathophysiological framework and discuss potential therapeutic strategies targeting angiogenesis to help to counteract obesity.