Zoonoses, such as plague, are primarily animal diseases that spill over into human populations. While the goal of eradicating such diseases is enticing, historical experience validates abandoning eradication in favor of ecologically based control strategies (which reduce morbidity and mortality to a locally accepted risk level). During the 20th century, one of the most extensive plague-eradication efforts in recorded history was undertaken to enable large-scale changes in land use in the former Soviet Union (including vast areas of central Asia). Despite expending tremendous resources in its attempt to eradicate plague, the Soviet antiplague response gradually abandoned the goal of eradication in favor of plague control linked with developing basic knowledge of plague ecology. Drawing from this experience, we combine new gray-literature sources, historical and recent research, and fieldwork to outline best practices for the control of spillover from zoonoses while minimally disrupting wildlife ecosystems, and we briefly compare the Soviet case with that of endemic plague in the western United States. We argue for the allocation of sufficient resources to maintain ongoing local surveillance, education, and targeted control measures; to incorporate novel technologies selectively; and to use ecological research to inform developing landscape-based models for transmission interruption. We conclude that living with emergent and reemergent zoonotic diseases—switching to control—opens wider possibilities for interrupting spillover while preserving natural ecosystems, encouraging adaptation to local conditions, and using technological tools judiciously and in a cost-effective way.