Carnivore predation on livestock is a complex management and policy challenge, yet it is also intrinsically an ecological interaction between predators and prey. Human-wildlife interactions occur in socioecological systems in which human and environmental processes are closely linked. However, underlying human-wildlife conflict and key to unpacking its complexity are concrete and identifiable ecological mechanisms that lead to predation events. To better understand how ecological theory accords with interactions between wild predators and domestic prey, we developed a framework to describe ecological drivers of predation on livestock. We based this framework on foundational ecological theory and current research on interactions between predators and domestic prey. We used this framework to examine ecological mechanisms (e.g., density-mediated effects, behaviorally mediated effects, and optimal foraging theory) through which specific management interventions operate, and we analyzed the ecological determinants of failure and success of management interventions in 3 case studies: snow leopards (Panthera uncia), wolves (Canis lupus), and cougars (Puma concolor). The varied, context-dependent successes and failures of the management interventions in these case studies demonstrated the utility of using an ecological framework to ground research and management of carnivore-livestock conflict. Mitigation of human-wildlife conflict appears to require an understanding of how fundamental ecological theories work within domestic predator-prey systems.