Substance use disorders blight the lives of millions of people and inflict a heavy financial burden on society. There is a compelling need for new pharmacological treatments as current drugs have limited efficacy and other major drawbacks. A substantial number of animal and recent clinical studies indicate that the neuropeptide, oxytocin, is a particularly promising therapeutic agent for human addictions, especially alcohol use disorders. In preliminary trials, we found that oxytocin administered by the intranasal route, which produces some neuropeptide penetration into the CNS, potently blocked withdrawal and reduced alcohol consumption in heavy drinkers. A considerable body of earlier animal studies demonstrated that oxytocin inhibits tolerance to alcohol, opioids, and stimulants as well as withdrawal from alcohol and opioids. Based on these preclinical findings and our clinical results, we hypothesize that oxytocin may exert therapeutic effects in substance dependence by the novel mechanism of diminishing established tolerance. A newer wave of studies has almost unanimously found that oxytocin decreases self-administration of a number of addictive substances in several animal models of addiction. Reduction of established tolerance should be included among the potential explanations of oxytocin effects in these studies and changes in tolerance should be examined in future studies in relationship to oxytocin influences on acquisition and reinstatement of self-administration as well as extinction of drug seeking. Oxytocin efficacy in reducing anxiety and stress responses as well as established tolerance suggests it may be uniquely effective in reducing negative reinforcement (Koob's "dark side" of addiction) that maintains chronic substance use.