Adolescent substance use continues to be a prevalent problem and is a cause of morbidity, mortality, and high rates of resource utilization. The variability in presentations of drug intoxication can make accurate identification of the ingested substance, and thus efficient treatment, challenging. This issue provides a review of typical presenting signs, symptoms, and physical examination findings of commonly used drugs. Evidence-based recommendations are offered for a general approach to managing adolescent patients who present with drug intoxication, with specific guidance, when indicated.