ABSTRACT The majority of emerging infectious diseases have their source in animals, and emergence occurs at the human-animal interface, when infections in animals breach the species barrier to infect humans, the population in which they are often first identified. The response is often a series of emergency activities to contain and manage the infection in human populations, and at the same time to identify the source of the infection in nature. If an infection is found to have a source in animals, and if animals cause a continuous threat of human infection, culling is often recommended, with severe economic impact. Currently the animal and human medicine sectors are working toward interacting more closely at the animal-human interface through joint surveillance and risk assessment, and research is under way in geographic areas where emergence at the animal-human interface has occurred in the past. The goal of this research is to identify infectious organisms in tropical and other wild animals, to genetically sequence these organisms, and to attempt to predict which organisms have the potential to emerge in human populations. It may be more cost-effective, however, to learn from past emergence events and to shift the paradigm from disease surveillance, detection, and response in humans to prevention of emergence at the source by understanding and mitigating the factors, or determinants, that influence animal infection. These determinants are clearly understood from the study of previous emergence events and include human-induced changes in natural environments, urban areas, and agricultural systems; raising and processing of animal-based foods; and the roles of global trade, migration, and climate change. Better understanding of these factors gained from epidemiological investigation of past and present emergence events, and modeling and study of the cost-effectiveness of interventions that could result in their mitigation, could provide evidence necessary to better address the political and economic barriers to prevention of infections in animals. Such economically convincing arguments for change and mitigation are required because of the basic difference in animal health, driven by the need for profit, and human health, driven by the need to save lives.