The genome sequence of Yersinia pestis, the causative agent of plague, has been fully determined. The genome consists of a 4.65-megabase (Mb) chromosome and three plasmids of 96.2 kb, 70.3 kb, and 9.6 kb. The genome is unusually rich in insertion sequences and shows anomalies in GC base-composition bias, indicating frequent intragenomic recombination. Many genes seem to have been acquired from other bacteria and viruses, including adhesins, secretion systems, and insecticidal toxins. The genome contains around 150 pseudogenes, many of which are remnants of a redundant enteropathogenic lifestyle. The evidence of ongoing genome fluidity, expansion, and decay suggests Y. pestis is a pathogen that has undergone large-scale genetic flux and provides a unique insight into the ways in which new and highly virulent pathogens evolve. Yersinia pestis is primarily a rodent pathogen, usually transmitted subcutaneously to humans by the bite of an infected flea, but also transmitted by air, especially during pandemics. It is very closely related to Yersinia pseudotuberculosis, and it has been proposed that Y. pestis is a clone that evolved from Y. pseudotuberculosis 1,500–20,000 years ago. Thus, Y. pestis seems to have rapidly adapted from being a mammalian enteropathogen to a blood-borne pathogen of mammals that is also able to parasitize insects and has limited capability for survival outside these hosts. Horizontally acquired DNA may be significant in having enabled Y. pestis to adapt to new hosts; conversely, the identification of gene remnants produced through genome decay may be associated with a redundant enteric lifestyle. The genome sequence of Y. pestis reveals a pathogen that has undergone considerable genetic flux, with evidence of selective genome expansion by lateral gene transfer of plasmid and chromosomal genes, and subsequent initial stages of genome size reduction. These features correlate with a change in pathogenic niche, and therefore this genome sequence provides a unique insight into the genetic events associated with the emergence of a new pathogenic species. The newly emerged pathogen is highly virulent for humans, causing pandemics of systemic, and often fatal, disease, contrasting with the ancestral species that evolved to cause non-fatal enteritis in similar hosts.The genome sequence of Yersinia pestis, the causative agent of plague, has been fully determined. The genome consists of a 4.65-megabase (Mb) chromosome and three plasmids of 96.2 kb, 70.3 kb, and 9.6 kb. The genome is unusually rich in insertion sequences and shows anomalies in GC base-composition bias, indicating frequent intragenomic recombination. Many genes seem to have been acquired from other bacteria and viruses, including adhesins, secretion systems, and insecticidal toxins. The genome contains around 150 pseudogenes, many of which are remnants of a redundant enteropathogenic lifestyle. The evidence of ongoing genome fluidity, expansion, and decay suggests Y. pestis is a pathogen that has undergone large-scale genetic flux and provides a unique insight into the ways in which new and highly virulent pathogens evolve. Yersinia pestis is primarily a rodent pathogen, usually transmitted subcutaneously to humans by the bite of an infected flea, but also transmitted by air, especially during pandemics. It is very closely related to Yersinia pseudotuberculosis, and it has been proposed that Y. pestis is a clone that evolved from Y. pseudotuberculosis 1,500–20,000 years ago. Thus, Y. pestis seems to have rapidly adapted from being a mammalian enteropathogen to a blood-borne pathogen of mammals that is also able to parasitize insects and has limited capability for survival outside these hosts. Horizontally acquired DNA may be significant in having enabled Y. pestis to adapt to new hosts; conversely, the identification of gene remnants produced through genome decay may be associated with a redundant enteric lifestyle. The genome sequence of Y. pestis reveals a pathogen that has undergone considerable genetic flux, with evidence of selective genome expansion by lateral gene transfer of plasmid and chromosomal genes, and subsequent initial stages of genome size reduction. These features correlate with a change in pathogenic niche, and therefore this genome sequence provides a unique insight into the genetic events associated with the emergence of a new pathogenic species. The newly emerged pathogen is highly virulent for humans, causing pandemics of systemic, and often fatal, disease, contrasting with the ancestral species that evolved to cause non-fatal enteritis in similar hosts.