The gram-negative bacterial envelope is a complex extracytoplasmic compartment responsible for numerous cellular processes. Among its most important functions is its service as the protective layer separating the cytoplasmic space from the ever-changing external environment. To adapt to the diverse conditions encountered both in the environment and within the mammalian host, Escherichia coli and Salmonella species have evolved six independent envelope stress response systems . This review reviews the sE response, the CpxAR and BaeSR two-component systems (TCS) , the phage shock protein response, and the Rcs phosphorelay system. These five signal transduction pathways represent the most studied of the six known stress responses. The signal for adhesion to abiotic surfaces enters the pathway through the novel outer membrane lipoprotein NlpE, and activation on entry into the exponential phase of growth occurs independently of CpxA . Adhesion could disrupt NlpE causing unfolding of its unstable N-terminal domain, leading to activation of the Cpx response. The most recent class of genes added to the Cpx regulon includes those involved in copper homeostasis. Two separate microarray experiments revealed that exposure of E. coli cells to high levels of external copper leads to upregulation of several Cpx regulon members. The BaeSR TCS has also been shown to mediate drug resistance in Salmonella . Similar to E. coli , the Bae pathway of Salmonella enterica mediates resistance to oxacillin, novobiocin, deoxycholate, β-lactams, and indole.