This dissertation is a political, social, and environmental history of the easternmost portion of the Orinoco River Basin (present-day Venezuela and Guyana), which I call the lower Orinoco, in the 1600s and 1700s. It integrates and analyzes Spanish efforts to colonize and exploit the region, the dynamism of the region’s constituent environments, and the politics and economics of the region’s resident Indians, runaway slaves, missionaries, and contrabandists. Drawing on documents mostly produced by military officers, colonial bureaucrats, mariners, and missionaries, it presents the lower Orinoco as an unruly, peripheral territory with an entangled Atlantic history: a Spanish dominion full of geopolitical contests, economic activities (mostly illicit), freedom struggles, and socio-environmental exchanges and adaptations. If the Spanish Crown envisioned the lower Orinoco as a site of great geopolitical consequence and colonial potential; the region’s isolation, intractability, and inter-imperial situation ultimately confounded Spanish colonization and supported extensive relations among local and interloping peoples. By revealing these hidden histories, this dissertation demonstrates how the lower Orinoco presented opportunities and obstacles to imperial and subaltern ventures, and it illuminates the history of a transboundary region that emerged in the absence of effective state power.