This article advances ideas presented at a National Academies of Sciences, Engineering, and Medicine workshop in 2022 that highlighted clinical practice and policy recommendations for delivering universal, family-focused substance use preventive interventions in pediatric primary care. Pediatric primary care is a natural setting in which to offer families universal anticipatory guidance and links to systematic prevention programming; also, several studies have shown that offering effective parenting programs in primary care is feasible. The article describes a blueprint for designing a pragmatic national agenda for universal substance use prevention in primary care that builds on prior work. Blueprint practice schematics leverage efficacious family-focused prevention programs, identify key program implementation challenges and resources, and emphasize adopting a core element approach and utilizing digital interventions. Blueprint policy schematics specify avenues for improving cross-sector policy and resource alignment and collaboration; expanding, diversifying, and strengthening the prevention workforce; and enhancing financing for family-focused prevention approaches. The article then draws from these schematics to assemble a candidate universal prevention toolkit tailored for adolescent patients that contains four interlocking components: education in positive parenting practices, parent and youth education in substance use risks, a parent-youth structured interaction task, and parent and youth linkage to in-person and web-based prevention resources.