Recent insights into bacterial genome organization and function have improved our understanding of the nature of pathogenic bacteria and their ability to cause disease. It is becoming increasingly clear that the bacterial chromosome constantly undergoes structural changes due to gene acquisition and loss, recombination, and mutational events that have an impact on the pathogenic potential of the bacterium. Even though the bacterial genome includes additional genetic elements, the chromosome represents the most important entity in this context. Here, we will show that various processes of genomic instability have an influence on the many manifestations of infectious disease.