Opiates produce their strong analgesic and addictive actions by activating mu-, delta-, and kappa-opioid receptors, which otherwise interact with endogenous opioid peptides to regulate nociception, mood, and responses to stress. The recent cloning of an opioid receptor gene family has allowed the production of null-mutant mice for each mu-, delta-, and kappa-receptor gene. Initial observation of receptor-deficient mice shows no obvious developmental abnormality, and reveals subtle modifications of pain perception in adult mice. Pharmacologic responses to standard opiates have been evaluated carefully, and results suggest that morphine produces its main biologic actions by acting specifically at mu-receptors, whereas delta-agonists seem weakly delta-selective under in vivo experimental conditions. Future studies of single- and combinatorial-opioid receptor-deficient mice will clarify the specific role of each receptor in chronic pain, motivation, and addictive behaviors. These mice also represent useful tools in the development of novel opioid compounds of therapeutic interest.