This chapter explores the mission’s vital antecedents by employing a transatlantic comparison of the ways in which religion served as a marker of sovereign power, connected violence to theologies of imperialism, and offered sanctuary amid the disruptions of unprecedented transatlantic contacts. Three lines of inquiry form the basis of this chapter. First, I examine religion as an expression of political sovereignty in fifteenth-century Mesoamerica and Iberia. Second, I address the most fundamental differences between Iberia and Mesoamerica. In Iberia, religious exclusivism fuelled a Spanish theological imperialism that sought to extend Catholicism to the exclusion of all competing god and religious institutions, while Mesoamerican empires integrated defeated gods to their pantheon. Part three, meanwhile, examines the way in which unprecedented cycles of encounter, conquest violence, widespread enslavement, and severe demographic crises in the Canaries and the Caribbean also made the mission a sanctuary from the worst depredations of early colonization. The transatlantic roots of the Mexican mission enterprise consist of three interconnected but also contradicting elements: religion as an expression of political sovereignty, as a basis for repression and violence, and as a promise of protection.