The mammalian immune system includes a sophisticated array of antimicrobial mechanisms. However, successful pathogens have developed subversive strategies to detect, modulate, and/or evade immune control and clearance. Independent disciplines study host immunology and bacterial pathogenesis, but interkingdom signaling between bacteria and host during natural infection remains poorly understood. An efficient natural host infection system has revealed complex communication between Bordetella spp. and mice, identified novel regulatory mechanisms, and demonstrated that bordetellae can respond to microenvironment and inflammatory status cues. Understanding these bacterial signaling pathways and their complex network that allows precisely timed expression of numerous immunomodulatory factors will serve as a paradigm for other organisms lacking such a powerful experimental infection system. Display omitted Well adapted bacterial pathogens have evolved mechanisms to sense and respond to immune components and host molecules, enabling them to evade, manipulate, or escape their antimicrobial effects. Bacteria adapt to particular anatomical sites and inflammatory stages by sensing signals specific to each and changing gene expression accordingly. Two-component systems, sigma factors, sRNAs, and chaperones allow bacteria to respond to environmental changes by orchestrating gene expression to optimize their fitness. Sensing carbon dioxide, iron starvation, hormones, and likely many other signals can refine the precise expression of virulence factors. Optimal temporal and spatial expression of virulence factors allows effective manipulation of host immune responses, and allows bacteria to efficiently colonize, infect, persist, and increase transmission amongst hosts.