A major proportion of the disease burden and deaths for young people in developed nations is attributable to misuse of alcohol and illicit drugs. Patterns of substance use established in adolescence are quite stable and predict chronic patterns of use, mortality, and morbidity later in life. We integrated findings of systematic reviews to summarise evidence for interventions aimed at prevention and reduction of harms related to adolescent substance use. Evidence of efficacy was available for developmental prevention interventions that aim to prevent onset of harmful patterns in settings such as vulnerable families, schools, and communities, and universal strategies to reduce attractiveness of substance use. Regulatory interventions aim to increase perceived costs and reduce availability and accessibility of substances. Increasing price, restricting settings of use, and raising legal purchase age are effective in reducing use of alcohol and tobacco and related harms. Screening and brief intervention are efficacious, but efficacy of a range of treatment approaches has not been reliably established. Harm-reduction interventions are effective in young people involved in risky and injecting substance use.