Background: Early substance use among adolescents is a substantial concern. Research indicates early substance use initiation increases the risk of adolescent problem behaviors including substance use in adulthood and deleterious problem behaviors for family relationships and the community (Substance Abuse and Mental Health Services Administration, [SAMSHA], 2014). Targeting family relationships and parenting practices has the potential for preventing adolescent problem behaviors (Fosco, Stormshak, Dishion, & Winter, 2012). However, applying an implementation science approach to evidence-based family centered programs has been slow and challenging. Implementation science provides insights that can be applied in clinical practice to promote the uptake of evidence-based findings. Understanding how to better implement family-based preventive interventions has the potential to decrease adolescent substance use and other problem behaviors. Purpose: One purpose of this systematic review was to make a more current assessment of which family-based programs are most effective in preventing adolescent substance use and other problem behaviors. The second purpose was to gain a better understanding of implementation approaches and challenges for uptake into practice settings. Method: Three procedures were used in this study. First, a systematic search of databases following the Hammerstrøm, Wade, Jørgensen, & Hammerstrøm (2010) method to identify prevention intervention studies using randomized controlled trials (RCTs) was conducted. Second, a methodological review of each study was done using The Society for Prevention Research’s (SPR) Standards of Evidence criteria for determining efficacy (Gottfredson et al., 2015). This is the first systematic review to use the SPR criteria. The third procedure determined which interventions were successfully replicated and culturally adapted in both effectiveness and scale-up trials. Results: (1) Using the SPR criteria, the most efficacious interventions for preventing adolescent substance use and problem behaviors were school-based, used multiple prevention strategies, implemented booster sessions, and focused on developing healthy peer relationships and substance refusing skills early in the adolescent’s life. The Strengthening Families Program (SFP) and The Family Check-Up (FCU) were the two interventions that met the criteria above. (2) Challenges in utilizing the SPR criteria included lack of guidelines to measure or assess the weight of one criterion versus another and no minimum guidelines for efficacious effect size. (3) Implementation challenges included waning educator enthusiasm, lack of training and fidelity, and insufficient funding. (4) Family engagement was a continuing challenge. Conclusions/Implications: (1) Schools provides a unique setting for prevention with access to multiple contexts. School-based prevention programs that target peer and family contexts should be widely disseminated, initiated early, and continued throughout adolescence into emerging adulthood. (2) Fragmented evaluation methods allow ineffective programs to enter national evidenced-based registries. A universal framework should be developed needs to separately evaluate implementation integrity and intervention validity. (3) School-based prevention efforts are fragmented and facing several implementation challenges. Social work efforts should focus on working with educators to make school-based prevention and training a priority. not a priority. (4) Programs should target family engagement challenges such as providing transportation and/or home-based services to help encourage families to initiate and complete prevention programs.