Periplasmic thiol/disulfide oxidoreductases participate in the formation and isomerization of disulfide bonds and contribute to the virulence of pathogenic microorganisms. Among the systems encoded in the genome, the system encoded by the locus was shown to be required to cope with Cu and HO stress. Here we report that this locus forms an operon whose transcription is driven by a promoter upstream of and depends on CpxR/CpxA and on Cu. Furthermore, genes homologous to, , and are always detected immediately downstream of and in the same genetic arrangement in all-harboring enterobacterial species. Also, a CpxR-binding site is detected upstream of in most of those species, providing evidence of evolutionarily conserved function and regulation. Each individual gene shows a different role in copper and/or HO resistance, indicating hierarchical contributions of these factors in the defense against these intoxicants. A protective effect of Cu preincubation against HO toxicity and the increased Cu-mediated activation of in the Δ mutant suggest that the CpxR/CpxA-controlled transcription of the ScsABCD system contributes to prevent Cu toxicity and to restore the redox balance at the envelope. Copper intoxication triggers both specific and nonspecific responses in The locus, which codes for periplasmic thiol/disulfide-oxidoreductase/isomerase-like proteins, has been the focus of attention because it is necessary for copper resistance, oxidative stress responses, and virulence and because it is not present in nonpathogenic Still, the conditions under which the locus is expressed and the roles of its individual components remain unknown. In this report, we examine the contribution of each Scs factor to survival under HO and copper stress. We establish that the genes form a copper-activated operon controlled by the CpxR/CpxA signal transduction system, and we provide evidence of its conserved gene arrangement and regulation in other bacterial pathogens.