RAGE [receptor for AGEs (advanced glycation end-products)] plays an important role in the development and progression of vascular disease. Studies in cultured cells and small animal models of disease have clearly demonstrated that RAGE is central to the pathogenesis of vascular disease of the macro- and micro-vessels in both the diabetic and non-diabetic state. Emerging results from human clinical studies have revealed that levels of circulating soluble RAGE in the plasma may reflect the presence and/or extent of vascular disease state. Additionally, genetic variants of the RAGE gene (AGER in HUGO nomenclature) have been associated with vascular disease risk. Combining RAGE circulating protein levels and the presence of particular RAGE polymorphisms may be a useful clinical tool for the prediction of individuals at risk for vascular disease. Therapeutic intervention targeted at the RAGE gene may therefore be a useful means of treating pathologies of the vasculature.