More than one quarter of Australian teenagers put themselves at risk of short-term alcohol-related harm at least once a month and 17% use an illicit drug at least once a year. As such, the need for prevention is clear. Although an array of school-based prevention programs exist, the majority show minimal effects in reducing drug use and related harms, and some have even report iatrogenic effects. Given that school–based drug prevention is the primary means by which drug education is delivered, it is essential to focus on increasing program efficacy. Ideally, preventive interventions should aim to delay onset in both adolescents with low-risk profiles who may be influenced to take up substances due to peer influence and social conformity, and adolescents with high-risk profiles whose underlying vulnerability to psychopathology can lead to substance misuse. Yet, there appear to be no models of well implemented programs that do this. The current proposal addresses this gap by developing and evaluating a comprehensive approach to preventing substance use and related harms in adolescents by combining effective ‘universal’ and ‘targeted’ school-based prevention programs. The proposed model, known as the CAP (Climate and Preventure) intervention, builds on our unique success in this area through developing the effective universal Climate, and targeted Preventure programs.