This article describes a program of prevention and intervention research conducted by the CHAMP (Collaborative HIV prevention and Adolescent Mental health Project; McKay & Paikoff, 2007) investigative team. CHAMP refers to a set of theory-driven, evidence-informed, collaboratively designed, family-based approaches meant to address the prevention, health, and mental health needs of poverty-impacted African American and Latino urban youth who are either at risk for HIV exposure or perinatally infected and at high risk for reinfection and possible transmission. CHAMP approaches are informed by theoretical frameworks that incorporate an understanding of the critical influences of multilevel contextual factors on youth risk taking and engagement in protective health behaviors. Highly influential theories include the triadic theory of influence, social action theory, and ecological developmental perspectives. CHAMP program delivery strategies were developed via a highly collaborative process drawing upon community-based participatory research methods in order to enhance cultural and contextual sensitivity of program content and format. The development and preliminary outcomes associated with a family-based intervention for a new population, perinatally HIV-infected youth and their adult caregivers, referred to as CHAMP+, is described to illustrate the integration of theory, existing evidence, and intensive input from consumers and healthcare providers.