Abstract Alcohol, tobacco, and other drug abuse (ATODA) is a critical public health issue. Research suggests that there are some principles that can guide effective prevention activities. This chapter explores not only what content should be included in such prevention activities, but also what processes and which contexts are best suited for optimal results. In general, research supports the use of developmentally appropriate activities that decrease risk factors and increase protective factors. Certain skills such as relationship skills and drug refusal skills are shown to be effective components of prevention work. Components that have not been successful include: affective skills training and the didactic imparting of drug information to elementary school students. Specific culturally responsive techniques are required for students of color, as the drug use profiles and risk/protective factors differ by ethnic/racial groups. A discussion of the political and fiscal contextual variables that impact the delivery of prevention activities is also presented.