This chapter reviews the major theories of drug use progression and their implications for prevention in adolescents, including the gateway model, the general liability model, and the developmental cascade model. Prevention interventions designed for universal (e.g., school-based, environmental), selective (e.g., family-focused), and indicated approaches (e.g., targeting heavy college drinkers) are reviewed, including programs that include all three levels (e.g., Family Check-Up, Triple-P). All of these approaches have been found to have both short-term and long-term efficacy. Challenges remain in disseminating these interventions on a wide scale, and many communities employ weaker programs when stronger ones are available. Potential pathways to achieve greater adoption of effective programs are outlined.