Escherichia coli O157 and other enterohemorrhagic E. coli (EHEC) are food- and waterborne zoonotic pathogens that cause diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome in humans but little or no discernible disease in their animal reservoirs. Like other zoonotic infections, EHEC are illustrative of the One Health concept as they embody the complex ecology of agricultural animals, wildlife, and the environment in zoonotic transmission of EHEC O157. But compared to the detailed epidemiological and clinical information available for EHEC infection in humans, there is an incomplete understanding of the ecology of EHEC infection in animals and the persistence of EHEC bacteria in the environment. Significant aspects of the microbiology, epidemiology, and host-pathogen interactions of EHEC in animals remain undefined. This review highlights the nature of EHEC infection in humans, provides a One Health perspective on what is known about EHEC in animal and environmental reservoirs, and proposes interventions targeted at pathways of transmission to optimize effective prevention and control measures.