Increasing numbers of youth globally live with a chronic illness. These youth use alcohol and marijuana at levels equal to or greater than their healthy peers and, when using, are at elevated risk for regular or problem use and adverse consequences to their condition. Little is known about whether behavioral theories commonly invoked to explain adolescent substance use apply to this group, limiting our ability to develop, tailor and target preventive interventions. We interviewed youth ages 16–19 years in care for a chronic disease to gain knowledge of this group’s perspectives on substance use risk, decision-making, and preferences for clinical guidance. Interviews were transcribed and thematically analyzed. Three principal themes emerged: first, having a chronic disease frames understanding of and commitment to health protecting behaviors and impacts decisions to avoid behaviors that carry risks for disease complications and flares; second, developmental impulses typical of adolescence can amplify an adolescent’s propensity to take risks despite medical vulnerability and direct youth toward maladaptive choices to mitigate risk; and third, poor knowledge about effects of substance use on specific features of a disease shapes perceived risk and undermines health protecting decisions. Youth navigate these issues variously including by avoiding substance use at a specific time or entirely, using while cognitively discounting risks and/or adjusting treatment outside of medical advice. Their perceptions about substance use are complex and reveal tension among choices reflecting a chronic illness frame, developmental impulses, and knowledge gaps. Delivery of targeted guidance in healthcare settings may help youth navigate this complexity and connect patient-centered goals to optimize health with health protecting behavioral decisions.