Adaptation to the environment is essential for pathogenic bacteria during the infection of host tissues. Remodeling of the lipid A portion of lipopolysaccharides in the outer membrane is involved in the adaptation of Gram-negative bacteria. Modifying lipopolysaccharides which are also known as endotoxins help pathogenic bacteria to increase their resistance to host-derived antimicrobial peptides as well as to evade host immune surveillance by Toll-like receptor 4-MD2 complex. In Salmonella typhimurium, the expression of lipid A modification enzymes is regulated by a two-component regulatory system, PhoP-PhoQ, formed from sensor kinase PhoQ and cognate response regulator PhoP. In addition to the transcriptional regulation, recent studies have accumulated evidence that outer membrane conditions greatly affect the activity of outer membrane lipid A modification enzymes, including PagL, PagP, and LpxR. The PhoP-activated gene product PagL encodes lipid A 3-O-deacylase. Lipid A deacylation decreases endotoxin activity, suggesting that the deacylation helps bacteria to evade host immune surveillance. However, lipid A deacylation is usually not observed, because PagL is latent in the outer membrane. Membrane aminoarabinose-modification, which changes cell surface charge, is essential for latency. Alanine-scanning mutagenesis of extracellular loops of PagL revealed that cationic amino acid residues, including Arg-43 and Arg-135, are involved in recognition of the aminoarabinose-modification. These findings suggest that PagL is a sensor as well as an enzyme. These observations constitute an emerging paradigm of outer membrane enzyme regulation. This paper focuses on the regulation and functions of outer membrane lipid A modification enzymes in S. typhimurium.