Abstract: This week's Review Article tackles the question of the evolution of human pathogens. Analysis of what we know of the origins of 10 tropical and 15 temperate infectious diseases reveals that animals were the source of the majority of important human diseases in the recent past, and that direct contact with animals through activities such as hunting remains a major route for disease acquisition. Modern developments such as industrial food production, vaccine production and blood transfusion may be making us more vulnerable than ever to new pathogens. The authors argue that people with high exposure to wild animals, such as hunters, zoo workers and wildlife veterinarians, should be regularly screened for emergent pathogens.This would provide early warning of newly introduced disease, and supply a repository of tissue samples that would assist in reconstructing the origin of later outbreaks. Many of the major human infectious diseases, including some now confined to humans and absent from animals, are ‘new’ ones that arose only after the origins of agriculture. Where did they come from? Why are they overwhelmingly of Old World origins? Here we show that answers to these questions are different for tropical and temperate diseases; for instance, in the relative importance of domestic animals and wild primates as sources. We identify five intermediate stages through which a pathogen exclusively infecting animals may become transformed into a pathogen exclusively infecting humans. We propose an initiative to resolve disputed origins of major diseases, and a global early warning system to monitor pathogens infecting individuals exposed to wild animals.