This chapter highlights the current literature vis-a-vis periplasmic mechanisms of antimicrobial and stress resistance and periplasmic constituents of signaling pathways that influence expression of resistance (periplasmic and other) determinants. An unrelated periplasmic heavy metal (Zn, Cu, Co, Ni)-binding protein, CzcE, is also encoded by the czc locus in Wautersia metallidurans, although it appears not to function in CzcCBA-mediated heavy metal efflux, its loss in mutant strains having no impact on resistance. A variety of mutant and gene-splicing studies have confirmed that the periplasmic domains of the CM-spanning resistance-nodulation-division (RND) components of tripartite RND-membrane fusion protein (MFP)-OM factor (OMF) pumps are responsible for substrate recognition. The observation that the Cu sensitivity of E. coli CopA ATPase mutants is not ameliorated by the presence of CusCFBA argues that this RND-type efflux system is unable to replace CopA in exporting Cu+ from the cytosol, its efflux activity apparently restricted to periplasmic Cu+. Bacteria sense their immediate environments and trigger appropriate responses through the up- or down-regulation of specific genes and/or their products. Many of the determinants of heavy metal resistance, including those involved in efflux and metal trafficking/detoxification, are metal inducible and this is mediated by two-component regulatory systems responsive to the metal substrates of these resistance determinants. Finally, the plethora of periplasmic enzymes for protection against ROS emphasizes the significance of environmental oxidative stress in the life of gram-negative bacteria, and while these are promoted as virulence determinants, it is far from clear that this is their only function.