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Urotensin-II (U-II), identified as a fish neuropeptide, exerts a broad spectrum of biological actions in mammals. Because the U-II isopeptide family is highly conserved across species, both amongst invertebrates and vertebrates, it has been inferred that U-II and its G-protein-coupled receptor,UT play a seminal role in the physiological regulation of major mammalian organ systems, most notably within the cardiovasculature. Can the identification of a fish peptide as a ligand for an 'orphan' mammalian G-protein-coupled receptor really tell us something about human physiology? Emerging preclinical and clinical data suggest that it might.