This review focused on the following four issues: 1) mentoring’s effects on substance use and associated risks to personal health and well-being; 2) factors that condition or influence the effects of mentoring on substance use and associated risks; 3) the intervening processes that are most important for linking mentoring to beneficial effects on substance use and associated risks; and 4) the extent to which youth mentoring programs that have focused on substance use prevention and intervention have been implemented with high quality and been adopted and sustained by host organizations and settings. Overall, the review found few studies that focused on the impact of youth mentoring on substance use prevention, and those that did have focused on commonly used substances such as alcohol and marijuana. Less attention has been given to the impact of mentoring on preventing the initiation or use of hard drugs, including opiates; therefore, there is limited evidence that shows tentative promise for mentoring to have a positive effect on the prevention and reduction of substance use among youth. The review notes, however, that studies of natural or informal mentoring showed significant positive effects more than studies of the impact of programmatic mentoring. Building on youth’s existing social resources and contacts with adult role models may be an important resource for preventing adolescent substance use. Online access is provided to resources and additional reading.