Substance use and related disorders are among the leading causes of preventable injury and illness, chronic health conditions, medical complications, disability, increased suffering, and premature death. Primary care clinicians can help patients avoid, reduce, or eliminate high-risk behaviors and negative consequences associated with substance use by integrating prevention and screening, brief intervention, and referral to treatment into their clinical practices. This article provides the necessary information, evidence-based recommendations, and readily available resources to help address substance use and related disorders in primary care, with special emphasis on the use of tobacco, alcohol, cannabis, and nonmedical prescription opioid medications.