Urotensin II (U-II) is a vasoactive hormone that acts through a recently described seven transmembrane-spanning G-protein-coupled receptor called GPR14. Although touted as the most potent vasoconstrictor peptide yet identified, the responses elicited by U-II are species-, tissue- and endothelium-dependent. Available data question the contribution of U-II to resting cardiovascular homeostasis in humans; instead they point to a role for this hormone in disease (heart failure and cardiac cell growth, renal function, diabetes, and mitogenesis in vascular and tumour cells). Key features of these diseases are increased expression and activity of U-II receptors. In this review, we focus on recent evidence that supports a role of U-II and its receptor in cardiovascular disease.