Although human behavior is frequently cited as a factor influencing the emergence of disease at the human–animal interface, few empirical studies have demonstrated this relationship. We compare humans and their domestic animals living in close proximity to populations of the endangered African wild dog (AWD, Lycaon pictus) in both Kenya and Botswana. We identify culturally based differences in domestic-stock grazing practices among pastoralists that strongly influence frequency of contact between domestic dogs and AWDs, with parallel differences in disease-related mortality in AWD populations. Using this study and other examples, we illustrate a conceptual model of the interaction between human behavior and emerging infectious diseases at the human–domestic-animal–wildlife interface. Human cultural behavior has the potential to influence pathogen adaptation, host susceptibility, spatial distribution, and pathogen exposure and contact rates between susceptible hosts, reservoir hosts, and pathogen communities. This affects the pathogen's basic reproductive number (R0), ability to invade, and persistence potential. Human behavior may be the key that unlocks the proverbial Pandora's Box, allowing infectious diseases to emerge.