The endothelium acts as a gatekeeper, controlling the movement of biomolecules between the circulation and underlying tissues. Although conditions of metabolic stress are traditionally considered as causes of endothelial dysfunction, a principal driver of cardiovascular disease, accumulating evidence suggests that endothelial cells are also active players in maintaining local metabolic homeostasis, in part, through regulating the supply of metabolic substrates, including lipids and glucose, to energy-demanding organs. Therefore, endothelial dysfunction, in terms of altered trans-endothelial trafficking of these substrates, may in fact be an early contributor towards the establishment of metabolic dysfunction and subsequent cardiovascular disease. Understanding the molecular mechanisms that underpin substrate trafficking through the endothelium represents an important area within the vascular and metabolism fields that may offer an opportunity for identifying novel therapeutic targets. This mini-review summarises the emerging mechanisms regulating the trafficking of lipids and glucose through the endothelial barrier and how this may impact on the development of cardio-metabolic disease.