Since its first identification in 1894 during the third pandemic in Hong Kong, there has been significant progress in understanding the lifestyle of Yersinia pestis, the pathogen that is responsible for plague. Although we now have some understanding of the pathogen’s physiology, genetics, genomics, evolution, gene regulation, pathogenesis and immunity, there are many unknown aspects of the pathogen and its disease development. Here, we focus on some of the knowns and unknowns related to Y. pestis and plague. We notably focus on some key Y. pestis physiologic and virulence traits that are important for its mammal-flea-mammal life cycle, but also its emergence from the enteropathogen, Yersinia pseudotuberculosis. Some aspects of the genetic diversity of Y. pestis, the distribution and ecology of plague, as well as the medical countermeasures to protect our population are also provided. Lastly, we present some biosafety and biosecurity information related to Y. pestis and plague.