Since its secularization in the 1830s, Mission Santa Clara de Asís and its associated grounds have seen major transformations. These changes include the gradual abandonment of the mission by its native inhabitants, the Californio and early Anglo-American use of mission structures, as well as the founding and growth of Santa Clara College (now Santa Clara University) and the City of Santa Clara. Through the analysis of historic maps, photographs, and archaeological findings, this paper provides an overview of the far-reaching physical changes that have fundamentally altered the original mission-era landscape, including the mission churches, cemeteries, and neophyte village. Information is drawn from historical and archaeological investigations into the lives of Native Americans at Mission Santa Clara, as well as an ongoing project I am conducting with undergraduate students and faculty from the departments of Anthropology and Environmental Studies and Sciences to record historic structures and other features in a geographic information system, or GIS. The massive scale of landscape changes over the past two centuries provide important context from which to consider the implications of future development on the preservation and study of the physical remnants of Mission Santa Clara.