Bacteria utilize varying combinations of twocomponent regulatory systems, many of which respond and adapt closely to stress conditions, thus expanding their niche steadily. While mechanisms of recognition and avoidance of the specific Fe 3+ signal by the PmrA/PmrB system is well understood, those of the CpxR/CpxA system are more complex because they can be induced by various stress conditions, which, in turn, expresses a variety of phenotypes. Here, we highlight another aspect of the CpxR/CpxA system; mutations in degP and yqjA genes, which are under the control of the system, exhibit an iron sensitive phenotype in the mutant background defective in the PmrA-dependent gene products that alter the pyrophosphate status of the lipid A moiety of lipopolysaccharide in Salmonella enterica. Therefore, after the PmrA/ PmrB-mediated Fe 3+ -dependent control of the pyrophosphate status on the cell surface, the CpxR/ CpxA system is one of the second layers of envelope stress response that allows adaptation to high Fe 3+ conditions in this bacterium.