Children from substance-affected families show an elevated risk for developing own substance-related or other mental disorders. Therefore, they are an important target group for preventive efforts. So far, such programs for children of substance-involved parents have not been reviewed together. We conducted a comprehensive systematic review to identify and summarize evaluations of selective preventive interventions in childhood and adolescence targeted at this specific group. From the overall search result of 375 articles, 339 were excluded, 36 full texts were reviewed. From these, nine eligible programs documented in 13 studies were identified comprising four school-based interventions (study 1–6), one community-based intervention (study 7–8), and four family-based interventions (study 9–13). Studies’ levels of evidence were rated in accordance with the Scottish Intercollegiate Guidelines Network (SIGN) methodology, and their quality was ranked according to a score adapted from the area of meta-analytic family therapy research and consisting of 15 study design quality criteria. Studies varied in program format, structure, content, and participants. They also varied in outcome measures, results, and study design quality. We found seven RCT’s, two well designed controlled or quasi-experimental studies, three well-designed descriptive studies, and one qualitative study. There was preliminary evidence for the effectiveness of the programs, especially when their duration was longer than ten weeks and when they involved children’s, parenting, and family skills training components. Outcomes proximal to the intervention, such as program-related knowledge, coping-skills, and family relations, showed better results than more distal outcomes such as self-worth and substance use initiation, the latter due to the comparably young age of participants and sparse longitudinal data. However, because of the small overall number of studies found, all conclusions must remain tentative. More evaluations are needed and their quality must be improved. New research should focus on the differential impact of program components and delivery mechanisms. It should also explore long-term effects on children substance use, delinquency, mental health, physical health and school performance. To broaden the field, new approaches to prevention should be tested in diverse cultural and contextual settings.