Several studies show that the nociceptin receptor NOP plays a role in the regulation of reward and motivation pathways related to substance abuse. Administration of the NOP's natural peptide ligand, Nociceptin/Orphanin FQ (N/OFQ) or synthetic agonist Ro 64-6198 has been shown to block rewarding effects of cocaine, morphine, amphetamines and alcohol, in various behavioral models of drug reward and reinforcement, such as conditioned place preference and drug self-administration. Administration of N/OFQ has been shown to reduce drug-stimulated levels of dopamine in mesolimbic pathways. The NOP-N/OFQ system has been particularly well examined in the development of alcohol abuse in animal models. Furthermore, the efficacy of the mixed-action opioid buprenorphine, in attenuating alcohol consumption in human addicts and in alcohol-preferring animal models, at higher doses, has been attributed to its partial agonist activity at the NOP receptor. These studies suggest that NOP receptor agonists may have potential as drug abuse medications. However, the pathophysiology of addiction is complex and drug addiction pharmacotherapy needs to address the various phases of substance addiction (craving, withdrawal, relapse). Further studies are needed to clearly establish how NOP agonists may attenuate the drug addiction process and provide therapeutic benefit. Addiction to multiple abused drugs (polydrug addiction) is now commonplace and presents a treatment challenge, given the limited pharmacotherapies currently approved. Polydrug addiction may not be adequately treated by a single agent with a single mechanism of action. As with the case of buprenorphine, a mixed-action profile of NOP/opioid activity may provide a more effective drug to treat addiction to various abused substances and/or polydrug addiction.