Bacterial chromosomes are not fixed molecules; they evolve over the course of infections in human beings. During infection, a variety of strong selective pressures are exerted on the pathogen. The resulting genetic changes that occur in intestinal pathogens might influence clinical outcome and have an impact on diagnosis and epidemiology. Enterohemorrhagic Escherichia coli (EHEC) is a good example of this process. These zoonotic pathogens cause diarrhea, bloody diarrhea, and hemolytic uremic syndrome in human beings, whereas in their natural habitat they mostly are asymptomatic colonizers. Thus, EHEC must be able to quickly adapt from one milieu to another. The greatest challenge it might face is to infect human beings--profound chromosomal changes occur during the brief period that EHEC passes through the human gastrointestinal tract, leading to gains and losses of virulence determinants. The intensive study of human enteric factors that induce or modulate pathogen chromosome instability could provide important information about host-microbial interactions.