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The epidemiology of foodborne disease is changing. New pathogens have emerged, and some have spread worldwide. Many, including Salmonella, Escherichia coli O157:H7, Campylobacter, and Yersinia enterocolitica, have reservoirs in healthy food animals, from which they spread to an increasing variety of foods. These pathogens cause millions of cases of sporadic illness and chronic complications, as well as large and challenging outbreaks over many states and nations. Improved surveillance that combines rapid subtyping methods, cluster identification, and collaborative epidemiologic investigation can identify and halt large, dispersed outbreaks. Outbreak investigations and case-control studies of sporadic cases can identify sources of infection and guide the development of specific prevention strategies. Better understanding of how pathogens persist in animal reservoirs is also critical to successful long-term prevention. In the past, the central challenge of foodborne disease lay in preventing the contamination of human food with sewage or animal manure. In the future, prevention of foodborne disease will increasingly depend on controlling contamination of feed and water consumed by the animals themselves.