Until recently, most information about substance use in the United States has come from large urban areas. Today, we recognize that substance use and the challenges that come from substance use disorders affect every region in the United States. Recent changes in our region in the rate of overdoses, the types of substances people are entering treatment for, and the changing health concerns around HIV and hepatitis C require that we pay more attention to substance use in rural areas of the US. Our mission is to understand the manifold experiences of people who use drugs in the rural Midwest. The center’s core 5-year study is made possible by the National Institute of General Medical Science’s Centers of Biomedical Research Excellence program. The RDAR center brings together researchers who focus on brain chemistry, social patterns of drug use, epigenetic understandings of biology and experience, and others. Working together, our goal is to understand the full range of the effects of substance use from the synapse through society. Our hope is that this research will help rural communities in our region understand regional substance use experiences and inform outreach, prevention, and treatment efforts.