Nociceptin/orphanin FQ (noc/oFQ) is the first novel bioactive substance to have been discovered by the implementation of a functional genomics/reverse pharmacology approach. The neuropeptide was indeed identified in brain extracts as the natural ligand of a previously cloned orphan G protein-coupled receptor, the opioid receptor-like 1 (ORL1) receptor. Since its discovery in 1995, noc/oFQ has been the subject of intensive study to establish its role in normal brain function and its possible involvement in neurophysiopathology. Although the neuropeptide, an inhibitor of neuronal activity, has been found to have a wide spectrum of pharmacological effects in vivo, none has been as intensively investigated as its action on nociception and nociceptive processing. There is now substantial evidence that noc/oFQ has a modulatory role in nociception. However, dependent on the dose and site of injection, and possibly the animal's genetic background and even psychological status, the peptide has been variously reported to cause allodynia, hyperalgesia, analgesia, and even pain, in rodents. Overall, noc/oFQ tends to facilitate pain when administered supraspinally, and to inhibit it when administered spinally. These opposing effects beg the obvious, yet still unanswered, question as to what would be the net effect on nociception of an ORL1 receptor ligand, agonist or antagonist, able to target supraspinal and spinal sites simultaneously. Owing to the research effort of several drug companies, such ligands, i.e. nonpeptidic, brain-penetrating agonists and antagonists, have recently been produced whose systematic screening in animal models of acute and inflammatory pain may help validate the ORL1 receptor as the target for novel, non-opioid analgesics.