This dissertation examines the ways in which indigenous peoples and missionaries, specifically Quakers (Society of Friends), contributed to the development of the American empire in the late eighteenth and nineteenth centuries. The U.S. civilization plan, in which Friends were central participants, offered agricultural education to American Indian men and, for women, instruction in the “domestic arts” as part of a broader mission complex. Far from being simply a means to “assimilate the Indians,” the mission complex was central to U.S. imperial and economic development, and its methods, endurance, and character grew out of a particular historical moment and as the result of a negotiation of Indians’ and Euroamericans’ goals and motivations. In order to investigate that negotiation, “Cultivating Empire” follows the evolution of diplomacy and agricultural mission work in the Ohio Country as a case study, and it draws upon individuals’ journals, family papers, account books and receipts, as well as missionary correspondences, meeting minutes from the Society of Friends, and various papers of federal, state, and territorial governments. Reading Euroamerican-produced sources against the grain in conjunction with sources such as Hendrick Aupaumut’s (Mohican) invaluable journals, moreover, offers means to bring indigenous politics to bear on this history, and it offers a top-down and bottom-up glimpse of the making of American empire. Such work reveals that the Society of Friends and its members, and their cooperation with the U.S. federal government, in many ways established the paradigm for the United States’ model of “philanthropic” empire beginning in the late eighteenth century. It also demonstrates that the society’s work was foundational for the development of the federal government’s relationship with non-governmental organizations and imperial policies abroad. Quaker diplomacy and agricultural missions also, however, offered Native peoples a powerful discourse and innovative means to continue to negotiate for power into the twenty-first century. U.S. state officials, Quaker missionaries, Euroamerican immigrants, and indigenous peoples together, then, produced the paradigms of U.S. empire in North America and the world in ways that had lasting consequences.