This article discusses the use of substances among adolescents, the unacceptable overdose death rates they bear, and the relevant evidence-based harm reduction strategies available in primary care, including medications for opioid use disorder. Access to these medications, as well as to harm reduction strategies generally, is insufficient for adolescents. Many adolescents who use substances and who are most at risk for overdose regularly visit primary care, which is an appropriate setting for treatment and harm reduction delivery.