Pharmacological studies and recent research using genetic approaches have indicated that most actions of exogenous opioids, such as morphine, are mediated through the mu-opioid receptor. By contrast, the function of the kappa-opioid receptor in opioid actions largely remains unclear. In this article, Zhizhong Z. Pan discusses the accumulating evidence that activation of the kappa-receptor antagonizes various mu-receptor-mediated actions in the brain, including analgesia, tolerance, reward and memory processes. The neural mechanism for this potentially ubiquitous mu-opposing function of the kappa-receptor is believed to involve distinct locations of the two opioid receptors on physiologically different cell types in local neuronal networks that are implicated in an opioid action.