During the mid-twentieth century, Soviet scientists developed the "natural focus" theory-practice framework to explain outbreaks of diseases (such as bubonic plague) endemic to wild animals and transmitted to humans. Focusing on parasitologist-physician Evgeny N. Pavlovsky and other field scientists' work in the Soviet borderlands, this article explores how the natural focus framework's concepts and practices were entangled in political as well as material ecologies of knowledge and practice. We argue that the very definition of endemic plague incorporated both hands-on materialist experience (including the identification of microbes/pathogens, insects/vectors, and mammals/reservoirs) and ideological concepts that supported Soviet colonization ("improving" hinterlands, "controlling natural focuses of disease," and "sanitizing" landscapes). Theorizing and fighting plague assisted with the goals of controlling and improving landscapes and peoples in southern Russia and Central Asia. The history of the natural focus framework illustrates how Soviet disease ecology co-developed with the needs of local and central political powers in the Soviet borderlands.