While political activists have long decried the cultural and economic marginalization of Appalachia in the twenty-first century, until now there has been no analogous effort to rectify the exclusion of Appalachia from the historiographical consideration of processes of colonial expansion, trans-Atlantic conflict, and genocide in the early modern Atlantic world. This lacuna in the telling of American history leads to an impoverished understanding of Appalachia's centrality in the European push inland from the North American coast beginning in the early sixteenth century. It also obscures from view how Appalachian treasure-hunting served as a key impetus for the atrocities perpetrated against Native Americans throughout the American southeast. This book highlights the repercussions of the European obsession with Appalachian mineral resources from 1528 to 1715, while reframing Appalachian history within the broader fields of Latin American, early American, and Atlantic history.