While political activists have long decried the cultural and economic marginalization of Appalachia in the twentieth and twenty-first centuries, Appalachia has similarly been excluded from the study of colonial expansion, transatlantic conflict, and slavery in the early modern Atlantic world. Drawing on sources in Spanish, Portuguese, French, Latin, and English, this monograph underscores the chaotically international, polyglot nature of early Appalachian history and foregrounds the region as a locus of imperial conflict during the early modern period. It likewise explores the European obsession with Appalachian mineral resources from 1528 to 1715, reframing Appalachian history within the fields of Latin American, early American, and Atlantic history. Ultimately, Appalachia as Contested Borderland of the Early Modern Atlantic provides new perspectives for scholars and students and suggests new directions for research in Native American and Indigenous studies, environmental studies, and Appalachian studies.