Public health scholars have long known that social, economic and cultural factors shape health outcomes. The Appalachian region exemplifies this interaction in the observable correlation between its health disparities and measures of socioeconomic status, such as educational achievement and poverty. This chapter assesses the social determinants of health in Appalachia using county-level data from a variety of national sources. It further contextualizes these findings using case studies of grassroots efforts across the region to address the social determinants of health. The chapter’s most important lesson is that improving regional health outcomes in Appalachia is a difficult task because poor social conditions appear unevenly; challenges in Central Appalachia are not replicated in the North, for example, meaning that policy-makers must implement solutions at the county level instead of treating the region monolithically.