All pathogenic bacteria possess the ability to evade or surmount body defenses (stresses, as experienced by the bacterium) long enough to cause a sufficient reaction, which is then manifested as a disease or illness. While opportunistic pathogens will only cause illness in the event of a predisposing weakness in these defenses, many pathogens must take on and overcome intact defenses. This is particularly true of gastrointestinal pathogens such as Listeria monocytogenes and Salmonella spp., which must circumvent many different stresses in order to arrive at the site of infection. These include the acid barrier of the stomach, the physical barrier of the epithelial cells lining the gastrointestinal tract, and various immune defenses including the initial onslaught of macrophages. Thus, these organisms have developed elaborate systems for sensing stress, and for responding to those stresses in a self-protective fashion. One well characterised adaptive response is to acid stress, the so-called acid tolerance response (ATR). The ATR is a complex phenomenon, involving a number of changes in the levels of different proteins and presumably, many allied events at the level of gene regulation. A number of molecular approaches have identified numerous interesting chromosomal loci involved both in sensing and responding to stress and in virulence. The identity of some of these genes, and their impact on stress responses and virulence will be discussed.