Drug use in youth is associated with multiple negative health and social consequences. Even infrequent use increases one's risk of serious adverse events due to an increase in risk-taking behaviors while intoxicated or impaired. Primary care could play a role in helping to prevent and reduce drug use in children and adolescents. In 2008, the U.S. Preventive Services Task Force (USPSTF) concluded that there was insufficient evidence to recommend for or against screening adolescents, adults, and pregnant women for illicit drug use. This recommendation was based on a staged evidence review of the literature published between 1994 and April 2006 and a 2008 supplemental assessment of screening instruments done on behalf of the USPSTF. The staged review only included research related to screening or treatment for marijuana, cocaine, or opioids and included evidence for children and adolescents, adults, and pregnant women. In contrast, the current systematic review focuses specifically on: 1) behavioral interventions that are considered feasible for primary care; 2) the primary prevention and reduction of all illicit drugs, including the nonmedical use of prescription drugs; and 3) children and adolescents age 18 years and younger only who do not meet criteria for substance abuse or dependence. The objective of this review is to systematically review evidence for the benefits and harms of primary care-relevant behavioral interventions designed to reduce illicit drug use or the nonmedical use of prescription drugs in children and adolescents.