In the context of the re-newed academic, political, and public interest in Area Studies, this article explores the spatial-political perspectives of inter-American Areas Studies. In a first step the article discusses the construction of the “area” of the Americas in regard to the triangular of power-space-knowledge. In a second step it proposes a framework to rethink hemispheric Area Studies relying on the concept of the Americas as space of entanglement. Thereby the article proposes three heuristic approaches towards a spatial framework of the space of entanglement. First, the concept of flows allows addressing the transregional mobilization and circulation of people, objects, commodities, and media. Second, geopolitical imaginaries allow us to understand the articulation of several spatial fragments into a broader concept of space and its representation. Third, with the emphasis on environment the article address the aspect of the materiality of space. The article ends with a plea for entangled methodologies in terms of pluritopical, transversal, dialogic, and horizontal approaches.