There are many reports showing prominent interactions between α2 adrenoceptor ligands and opioid drugs. This paper discusses these studies and the evidence available for their potential therapeutic applications. In acute conditions, α2-adrenoceptor antagonists inhibit some of the central and peripheral effects of opioids, while agonists have additive or synergistic effects that can be useful in enhancing opioid analgesia. Chronic administration of prescribed or illegal opioids leads to biological adaptations that influence the function of α2 adrenoceptors, which can be significantly modified by the ligands of these receptors: thus, cross-tolerance has been described between opioid and α2 agonists, and these latter drugs effectively block the manifestations of opioid withdrawal in animals and humans. Conversely, α2- adrenoceptor antagonists prevent the development of tolerance or dependence when coadministered with chronic opioids and increase withdrawal signs when acutely injected to abstinent subjects. There are also preclinical and clinical data showing that α2-adrenoceptor ligands could modify the appetitive and motivational properties of opioid drugs: agonists tend to increase these addictive properties, while the antagonist yohimbine has been shown to decrease opioid reinforcement in place conditioning studies. Interestingly, α2-adrenoceptor agonists prevent the reinstatement of opioid and cocaine self-administration induced by stress. All these studies tend to show that, if properly used, α2-adrenoceptor ligands could be useful both to potentiate the beneficial effects of opioids, and to limit the complications of opioid tolerance, dependence and addiction.