The observed clustering, and shared underlying determinants, of risk behaviours in young people has led to the proposition that interventions should take a broader approach to risk behaviour prevention. In this review we synthesized the evidence on ‘what works’ to prevent multiple risk behaviour (focusing on tobacco, alcohol and illicit drug use and sexual risk behaviour) for policy-makers, practitioners and academics. We aimed to identify promising intervention programmes and to give a narrative overview of the wider influences on risk behaviour, in order to help inform future intervention strategies and policies. The most promising programme approaches for reducing multiple risk behaviour simultaneously address multiple domains of risk and protective factors predictive of risk behaviour. These programmes seek to increase resilience and promote positive parental/family influences and/or healthy school environments supportive of positive social and emotional development. However, wider influences on risk behaviour, such as culture, media and social climate also need to be addressed through broader social policy change. Furthermore, the importance of positive experiences during transition periods of the child–youth–adult phase of the life course should be appropriately addressed within intervention programmes and broader policy change, to reduce marginalization, social exclusion and the vulnerability of young people during transition periods.