Urotensin II, a cyclic 11-13 residue peptide expressed in motoneurons of the spinal cord, acts as a potent vasoconstrictor. The effects of urotensin II are mediated by binding to a GPCR, GPR14, which is expressed in endothelium, smooth muscle, heart and pancreas. Genetic deletion of GPR14 in mice renders aortae refractile to the contractile activity of urotensin II without changing baseline hemodynamics. Pharmacological inhibition of urotensin II/GPR14 interactions prevents renal insufficiency following renal artery ligation. Thus, GPR14 is an attractive target for a number of cardiovascular diseases.