Substance use and abuse represent the most preventable cause of death. ~50% of individuals who are diagnosed with a mental illness will also meet criteria for a substance use disorder. The HEALTH Research Institute leverages team science to uncover mechanisms associated with substance use (e.g., alcohol, tobacco, marijuana, etc.) and the comorbidity with a range of mental health challenges (e.g., antisocial personality, anxiety, chronic stress, depression, trauma, etc.). We have designed novel culturally-informed prevention, treatment, and dissemination strategies that reduce transdiagnostic risk-factors and foster sustainable sobriety in individuals and institutions.