As the COVID-19 virus swept across the nation in spring 2020, infection and hospitalization rates in states like West Virginia remained relatively low. By that July, each of Appalachia's 423 counties had recorded confirmed cases. The coronavirus pandemic has taken an enormous toll on the health of individuals and institutions throughout the region—a stark reminder that even isolated rural populations are subject to historical, biological, ecological, and geographical factors that have continually created epidemics over the past millennia. In Appalachian Epidemics: From Smallpox to COVID-19, scholars from diverse disciplinary backgrounds assess two centuries of public health emergencies and the subsequent responses. This volume peers into the trans–Appalachian South's experience with illness, challenging the misconception that rurality provides protection against maladies. In addition to surveying the impact of influenza, polio, and Lyme disease outbreaks, Appalachian Epidemics addresses the less-understood social determinants of health. The effects of the opioid crisis and industrial coal mining complicate the definition of disease and illuminate avenues for responding to future public health threats. From the significance of regional stereotypes to the spread of misinformation and the impact of racism and poverty on public health policy, Appalachian Epidemics makes clear that many of the natural, political, and socioeconomic forces currently shaping the region's experiences with COVID-19 and other crises have historical antecedents.