Like their peers in the general youth population, youth with chronic medical conditions (YCMC) are at risk for substance use, including nonmedical use of prescription medications. However, given dangerous disease-substance interactions, the stakes for detecting and intervening on substance use are perhaps even higher for YCMC. Given the risk for nonadherence with chronic disease management, it is incumbent on primary care providers, specialty providers, and behavioral health specialists to be vigilant in asking about substance use and providing brief counseling and referral to substance use treatment when appropriate.