This report by the National Association of Counties and the Appalachian Regional Commission describes the impact of the opioid epidemic on Appalachian counties and offers recommendations for local action. These recommendations are discussed in five sections, each of which features key action steps and one or more case studies highlighting an Appalachian county: (1) leadership, (2) prevention, (3) recovery, (4) rehabilitation for justice-involved individuals, and (5) economic development. The recommendations and case studies contained in the report are designed to aid Appalachian county leaders in their efforts to formulate effective, efficient, and sustainable responses to the opioid epidemic.