The human-animal interface is as ancient as the first bipedal steps taken by humans. Born with the human species, it has grown and expanded with the human species' prehistoric and historical development to reach the unprecedented scope of current times. Several facets define the human-animal interface, guiding the scope and range of human interactions with animal species. These facets have not ceased to evolve and expand since their emergence, all the more favoring disease emergence. Placing the human-animal interface in its historical perspective allows us to realize its versatile and dynamic nature. Changes in the scope and range of domestication, agriculture, urbanization, colonization, trade, and industrialization have been accompanied by evolving risks for cross-species transmission of pathogens. Because these risks are unlikely to decrease, improving our technologies to identify and monitor pathogenic threats lurking at the human-animal interface should be a priority.