Over 20 orphan receptors predicted to exist from the human genome have now been paired with their cognate peptide ligand. In human tissues, expression of mRNA encoding several of these peptides (including bovine adrenomedullary peptide, orexins, prolactin-releasing peptide, tuberoinfundibular peptide 39 and neuropeptide B and W) and their receptors is predominantly in the CNS, implying a central role. However, ligand-binding and functional studies suggest that urotensin II, apelin, ghrelin, relaxin and urocortins, together with the trace amine tyramine, may have a role in the human cardiovascular system, with the prospect of becoming new therapeutic targets.