Extensive preclinical data support the proposal that KOR antagonists may have therapeutic benefit for the treatment of mood disorders and drug addiction by promoting stress resilience . People who are vulnerable to depression, anxiety, or addiction can become hypersensitive to stressful experience, which can act as a trigger for a recurrence of a mood disorder or substance use episode. The neuronal processes underlying these responses have been extensively studied in animal models where stress exposure can cause the release of stress neuropeptides including the endogenous dynorphins in brain, which activate KOR. Kappa receptor activation in animals and humans produces anxiety-like, dysphoric, aversive, and drug-seeking behavioral responses. Antagonists that block KOR can reduce these stress responses and thereby have antidepressant and anti-addictive activity in animal models. For example, kappa antagonists block stress-potentiation of drug reward, block drug-seeking in substance-dependent animals, and block stress-induced reinstatement of drug self-administration. These beneficial effects of kappa antagonists are evident in behavioral assays using a wide range of addictive substances . In addition, kappa antagonists are effective in the preclinical behavioral assays predictive of antidepressant efficacy in humans . Thus, kappa antagonists could theoretically have broad clinical utility, and the recognition of this opportunity has stimulated a new wave of drug development.