Project Summary: We propose a five-year prospective, longitudinal qualitative study that will characterize fentanyl-stimulant (cocaine, crack cocaine, methamphetamine) polysubstance use among people experiencing homelessness across two cities (New York, NYC; San Francisco, SF). More than 100,000 overdose deaths occurred in the US in the one-year period ending April 2021. Nearly half involved the co-use of opioids (primarily fentanyl) and stimulants. People experiencing homelessness report higher prevalence of fentanyl-stimulant polysubstance use and are more vulnerable to drug-related harms. Fentanyl-stimulant polysubstance use is a likely contributor to widening racial disparities in overdose mortality, and yet relationships between fentanyl- stimulant polysubstance use, drug-related harms, and racial health disparities are not well-understood. Similar to cities in the US, NYC and SF are experiencing rising homelessness and overdoses, especially among Black and Latinx populations. NYC and SF are implementing comprehensive overdose prevention and SUD treatment responses, including naloxone and drug-checking programs, MOUD expansion, and, recently in NYC, overdose prevention centers. Gender differences in engagement with these prevention and treatment services are understudied. Homelessness crises in both cities have catalyzed novel housing interventions. Yet, we lack the knowledge about relationships between polysubstance use and housing trajectories, drug-related harms, and engagement with overdose prevention and SUD treatment services that is needed to inform more effective responses to the overdose epidemic. Building on our extensive experience studying drug use patterns and their implications for drug-related harm, we propose the following specific aims: SA1: To characterize fentanyl- stimulant polysubstance use patterns among people experiencing homelessness and examine how these patterns evolve over time due to changes to housing status and engagement with overdose prevention and SUD treatment interventions. SA2: To explore how fentanyl-stimulant polysubstance use patterns shape overdose vulnerability over time among people experiencing homelessness. SA3: To implement an integrated stakeholder engagement process to translate qualitative findings to inform overdose prevention, SUD treatment, and housing strategies and future research targeting fentanyl-stimulant use. Informed by the equity-focused Intersectional Risk Environment framework, we will: (1) conduct baseline and annual follow-up qualitative interviews and ethnographic fieldwork (Years 1-4) with a cohort of fentanyl-stimulant-using people experiencing homelessness (n=120) sampled for racial and gender diversity (SA1&2); (2) conduct targeted qualitative interviews on emergent fentanyl-stimulant polysubstance use dynamics (Years 3&4); and (3) in collaboration with our Stakeholder Engagement Board, recruit a stakeholders cohort (n=50; people with lived experience, substance use and ho...