Microbes are able to sense and respond to their environment primarily through the use of two-component regulatory systems. Many of these systems activate virulence-factor expression and are regulated by host-derived signals, having evolved to control gene expression at the key time and place for optimal establishment and maintenance of infection. Salmonella spp. are enteric pathogens that are able to survive both within host macrophages during systemic spread and killing by innate immune factors at intestinal mucosal surfaces. This review focuses on a key mechanism of pathogenesis that involves the PmrA-PmrB two-component system, which is activated in vivo by direct or indirect means and regulates genes that modify lipopolysaccharide, aiding survival in host (and non-host) environments.