Alcohol and other substance use problems are common, and the efficacy of current prevention and intervention programs is limited. Genetics may contribute to differential effectiveness of psychosocial prevention and intervention programs. This paper reviews gene-by-intervention (G×I) studies of alcohol and other substance use, and implications for integrating genetics into prevention science. Systematic review yielded 17 studies for inclusion. Most studies focused on youth substance prevention, alcohol was the most common outcome, and measures of genotype were heterogeneous. All studies reported at least one significant G×I interaction. We discuss these findings in the context of the history and current state of genetics, and provide recommendations for future G×I research. These include the integration of genome-wide polygenic scores into prevention studies, broad outcome measurement, recruitment of underrepresented populations, testing mediators of G×I effects, and addressing ethical implications. Integrating genetic research into prevention science, and training researchers to work fluidly across these fields, will enhance our ability to determine the best intervention for each individual across development. With growing public interest in obtaining personalized genetic information, we anticipate that the integration of genetics and prevention science will become increasingly important as we move into the era of precision medicine.