The burden of morbidity and mortality from non-communicable disease has risen worldwide and is accelerating in low-income and middle-income countries, whereas the burden from infectious diseases has declined. Since this transition, the prevention of non-communicable disease as well as communicable disease causes of adolescent mortality has risen in importance. Problem behaviours that increase the short-term or long-term likelihood of morbidity and mortality, including alcohol, tobacco, and other drug misuse, mental health problems, unsafe sex, risky and unsafe driving, and violence are largely preventable. In the past 30 years new discoveries have led to prevention science being established as a discipline designed to mitigate these problem behaviours. Longitudinal studies have provided an understanding of risk and protective factors across the life course for many of these problem behaviours. Risks cluster across development to produce early accumulation of risk in childhood and more pervasive risk in adolescence. This understanding has led to the construction of developmentally appropriate prevention policies and programmes that have shown short-term and long-term reductions in these adolescent problem behaviours. We describe the principles of prevention science, provide examples of efficacious preventive interventions, describe challenges and potential solutions to take efficacious prevention policies and programmes to scale, and conclude with recommendations to reduce the burden of adolescent mortality and morbidity worldwide through preventive intervention.