Boasting a 3,000 year history and a status as the oldest continuously inhabited city in the Americas, present-day San Pedro Cholula in the central Mexican state of Puebla has always been imbued with the sacred. As early as 500 BC, its inhabitants began laying the foundations of what would become the Great Pyramid of Cholollan. By 700 AD, the structure's size surpassed the Pyramid of the Sun in the nearby religious center of Teotihuacan. Following a period of rapid decline, Olmeca-Xicalanca invaders from the south gained political dominance in the region. Vanquished in 1168 AD by Tolteca-Chichimeca from the north, the conquerors quickly established Quetzalcoatl as the new titular deity of Cholollan. Erecting a magnificent sanctuary to the Plumed Serpent, the newcomers effectively re-centered the spiritual and political focus of the altepetl (Mesoamerican city-state) from the Great Pyramid to their newly-constructed Quetzalcoatl Temple. By 1519, when the first Spaniards arrived, the pyramid was little more than a hillside haven for rabbits and deer, whereas the sanctuary had become the focus of ritual and pilgrimage in the region, with numerous teocalli, or indigenous temples, dotting the landscape. In addition to being renowned as a spiritual hub, by the sixteenth century Cholollan had developed into a nucleus of culture and learning as well as a center of long-distance trade with a vibrant marketplace specializing in exotic goods. The friars who arrived in 1529 capitalized on Cholollan's spiritual reputation to establish what would become the most important Franciscan evangelization complex in central New Spain; this resulted in the most radical outward transformation in Cholollan's sacred history: from Mesoamerican to Catholic. Reading archival materials from state and national archives in Mexico and Spain alongside sixteenth-century ethnohistorical sources, this paper examines the site-specific conversion methodologies employed by the early friars among a people long accustomed to regional spiritual domination. As overseers of the Quetzalcoatl cult, the native Cholulteca had also enjoyed pre-hispanic secular importance, conducting rituals of political legitimation in the Quetzalcoatl Sanctuary for neighboring indigenous leaders. Upon the establishment of Spanish colonial rule, the local Nahuas worked to retain Cholollan's sacred identity while simultaneously capitalizing on Franciscan presence for social, political, and personal gain. Ultimately, I argue that Cholollan's continued status as a holy site is as much due to indigenous agency as to Franciscan pragmatism.