Publisher Summary Bubonic plague caused by Yersinia pestis ranks as the most severe bacterial disease known to humanity. In the mouse, this bleak process consists of an initial invasive stage characterized by the colonization of the host viscera from the dermal sites of infection caused by fleabite. Thereafter, the organisms undergo bulk vegetative growth in liver and spleen before spilling into the vascular system, where they may again be ingested by fleas before the now imminent death of the host. A similar course occurs in humans, except that lymphadenopathy is more severe, as judged by the formation of buboes in regional lymph nodes that drain the vicinity of the infected fleabite. Yersinia pestis has three remarkable attributes: it causes the most severe of all human bacterial infections, survival and multiplication of the plague bacillus within the host and vector are largely mediated by three plasmids and at least one chromosomal high-pathogenicity island, and the emergence of Y. pestis has occurred in recent geological times and its evolution may still be in progress. This chapter integrates these three features and defines the molecular mechanisms that enable Y. pestis to promote uncompromisingly acute disease. Two additional Yersinia species pathogenic to humans provide an excellent foil for identifying the unique determinants of acute disease utilized by plague bacilli.