Adolescent use of illicit substances imposes an enormous burden on individuals, families, and communities. The types of illicit substances adolescents are using have changed drastically over the past decade with decreases in alcohol use (including binge alcohol use) offset by increases in electronic cigarette, marijuana, and opioid use. Primary care physicians have the opportunity to identify adolescents who use illicit substances. The U.S. Preventive Services Task Force and the American Academy of Family Physicians found insufficient evidence to assess the balance of benefits and harms of primary care-based behavioral interventions to prevent or reduce illicit substance use or nonmedical pharmaceutical use in children or adolescents. The American Academy of Pediatrics recommends that clinicians become familiar with Screening, Brief Intervention, and Referral to Treatment initiatives. Validated screening tools that may be used in primary care include the CRAFFT, POSIT, AUDIT, and NIAAA Screening Guide. During the clinical visit, a split-visit model encourages parents to participate in the visit for a limited time but also allows adolescents to have confidential conversations with physicians. Evidence-based treatment modalities range from school- and parent-based interventions to medication-assisted treatment. Brief interventions using components of motivational interviewing may be suitable for addressing substance use, even among adolescents not seeking treatment. Prevention efforts can supplement cessation programs to maximize program effectiveness.