Adolescent substance use is linked to an array of neurological (Squeglia, Jacobus, & Tapert, 2009), mental health (e.g., anxiety; Saraceno, Munafó, Heron, Craddock, & van den Bree, 2009), behavioral (e.g., sexual risk-taking; Miller, Levy, Spicer, & Taylor, 2006), and academic (Townsend, Flisher, & King, 2007) problems. Nonetheless, experimentation with substance use, and the initiation of alcohol, cigarette, and marijuana use in particular, is common among youth (Kann et al., 2014). Schools represent an important context in which substance use could be prevented, reduced, or even promoted, posing unique opportunities for intervention. Researchers have noted the limitations of traditional clinic-based service delivery methods in reaching a large number of adolescents that may be addressed via school-based assessments and interventions (see Wagner, Tubman,& Gil, 2004). The present chapter focuses on critical issues surrounding substance use (e.g.,prevalence, etiology, correlates) and evidence-based practices for assessment and intervention in school settings.