During adolescence, teenagers try a range of risk behaviors including smoking, drinking, and the use of soft drugs. Because substance use contributes to an unhealthy lifestyle of teenagers on the short term and can lead to serious health problems on the longer term, prevention in this target group is important. This chapter provides an overview of the determinants of substance use on the one hand, and primary and secondary prevention opportunities on the other hand, especially in the school context. At the end, future directions and recommendations for school, youth, and family are discussed.