Native American (NA) youth report higher rates of alcohol, marijuana, and drug use than U.S. adolescents from any other racial/ethnic group. Addressing this health disparity is a significant research priority across public health, minority health, and dissemination and implementation (D&I) sciences, underscoring the need for empirically-based interventions tailored for NA youth. Effective D&I with NA youth incorporates NA cultural values and involves tribal elders and stakeholders. SACRED Connections (NIDA R01DA02977) was a university-tribal research partnership that utilized a culturally derived Native-Reliance theoretical framework and a community-based participatory research (CBPR) approach. A significant objective of this randomized controlled trial was to close D&I gaps utilizing the RE-AIM Model and National Culturally and Linguistically Appropriate Services (CLAS) in Health and Health Care Standards (HHS, 2019). Findings of this 5-year RCT revealed a statistically significant protective relationship between Native Reliance and baseline lifetime and past month alcohol and marijuana use; additionally, the likelihood of reporting marijuana use at 3 months post-intervention was significantly lower among the active condition than among the control condition. Implementation of a developmentally and NA culturally tailored brief protocol revealed: partnering with Native Americans and utilizing CBPR facilitated engagement with this hard-to-reach, underserved community; age and culture are associated with substance use severity among NA teens; a culturally adapted Motivational Interviewing (MI) brief intervention may be effective in reducing marijuana use among NA youth; the Native Reliance theory proved useful as a framework for working with this population; and RE-AIM proved helpful in conceptualizing health equity promoting D&I.