The implication of the opioidergic system in the pathogenesis of various substance use disorders has led to renewed interest in expanding the clinical uses of naltrexone, an opioid antagonist. This article examines the evidence for the efficacy of naltrexone in a variety of substance use and psychiatric disorders. Naltrexone can be an effective treatment for alcohol and opioid dependence if issues of compliance are adequately addressed. Thus far, no definitive role has been found for naltrexone in the treatment of other psychiatric disorders. Further research needs to be done in self-injurious behavior, gambling, cocaine, and nicotine dependence.