Despite the importance of pneumonic plague caused by Yersinia pestis, a few is known about the interaction between Y. pestis and its host at the molecular level during the pneumonic plague development. In this study, we employed an intranasally challenged plague model in mice for investigating the kinetics of the disease progression by transcriptional profiling of Y. pestis and mice using qRT-PCR and microarray, respectively. The increasing transcription of important virulence genes of Y. pestis and of mice genes involving in immune and inflammatory defensive responses, and responses to stimuli, presents an overview of interaction between Y. pestis and mice during development of pneumonic plague. The early and persisting up-regulation of caf 1, psa A and lcr V in vivo indicated their role in resisting the host innate immune responses. The up-regulation of fur, ybt A and hms H in vivo reflected the ability of Y. pestis for acquiring iron. The transcription regulators, including pho P, oxy R and omp R, were up-regulated during plague development, suggesting their roles in interaction between Y. pestis and mice. Many genes encoding cytokines, such as IL2, IL-1B, CXCL2, CXCL5, CCL20, CD14 and TNFRSF13B, were up-regulated during the infection, confirming the report that they are important mediators to activate host responses to invading pathogens. The up-regulation of some genes encoding important virulent factors of Y. pestis and expression alterations of some genes encoding cytokines in the host reflect the interaction between the pathogen and the host, which will help us better understand plague pathogenesis.