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Opioid receptors of the μ-, δ- and κ-subtypes mediate the potent analgesic and addictive actions of opioid drugs. They also regulate responses to pain, stress and emotions when activated by endogenous opioid peptides. Recently, mice lacking opioid receptors or opioid peptides have been produced by gene targeting, providing molecular tools to study opioid function in vivo. Observations on mutant mice have shed new light on the mode of action of opioids, opioid receptor heterogeneity and interactions, and the involvement of each component of the opioid system in mouse physiology. In this article, Brigitte L. Kieffer reviews the first reported studies and discusses their therapeutic implications.