Yersinia pestis, the bacterial agent of bubonic plague, is transmitted primarily by fleas and has been responsible for devastating epidemics throughout history. Y. pseudotuberculosis is a food- and water-borne pathogen that causes a much more benign enteric disease in humans. Despite these profoundly different pathogenesis strategies, the two bacteria are very closely related phylogenetically. Thus, identifying the specific genetic differences between them should provide an instructive case study in the evolution of microbial pathogenicity. Some key pathogenesis-related genes of Y. pestis and Y. pseudotuberculosis that have been described to date are compared in this review. Factors that potentiate plague transmission as well as disease are discussed, since dependence on the blood-sucking flea for transmission likely fueled the selection of virulent Y. pestis strains able to produce a high-density bacteremia. Retracing the evolutionary steps between these two Yersinia species may ultimately furnish a historical model for the sudden emergence of new human disease agents.