The ability of gram-negative bacteria to resist killing by antimicrobial agents and to avoid detection by host immune systems often entails modification to the lipopolysaccharide (LPS) in their outer membrane. In this review, we examine the biology of the PmrA/PmrB two-component system, the major regulator of LPS modifications in the enteric pathogen Salmonella enterica. We examine the signals that activate the sensor PmrB and the targets controlled by the transcriptional regulator PmrA. We discuss the PmrA/PmrB-dependent chemical decorations of the LPS and their role in resistance to antibacterial agents. We analyze the feedback mechanisms that modulate the activity and thus output of the PmrA/PmrB system, dictating when, where, and to what extent bacteria modify their LPS. Finally, we explore the qualitative and quantitative differences in gene expression outputs resulting from the distinct PmrA/PmrB circuit architectures in closely related bacteria, which may account for their differential survival in various ecological niches.