Substance use and the contexts that surround it have caused real harm in Appalachia. Part of this pain may be attributed to substance use itself, but much is also due to our collective reaction to substance use and people who use drugs. The confluence of stigmas against Appalachians, people who are poor, and people who use drugs, as well as the intense surveillance of caregivers, have produced interpersonal violence within medical, social service, and legal systems, which the authors have documented in their geographically dispersed work. This discrimination lives within policies that negatively affect the health, economic opportunities, and family life of many Appalachians who are poor. As researchers and community health workers, we propose ways of moving forward that avoid further marginalizing vulnerable populations, particularly people who are caregivers and use drugs.