Acidity is one of the principal physicochemical factors that influence the behavior of microorganisms in any environment, and their response to it often determines their ability to grow and survive. Preventing the growth and survival of pathogenic bacteria or, conversely, promoting the growth of bacteria that are useful (in biotechnology and food production, for example), might be improved considerably by a deeper understanding of the protective responses that these microorganisms deploy in the face of acid stress. In this review, we survey the molecular mechanisms used by two unrelated bacterial species in their response to low pH stress. We chose to focus on two well-studied bacteria, Escherichia coli (phylum Proteobacteria) and Listeria monocytogenes (phylum Firmicutes), that have both evolved to be able to survive in the mammalian gastrointestinal tract. We review the mechanisms that these species use to maintain a functional intracellular pH as well as the protective mechanisms that they deploy to prevent acid damage to macromolecules in the cells. We discuss the mechanisms used to sense acid in the environment and the regulatory processes that are activated when acid is encountered. We also highlight the specific challenges presented by organic acids. Common themes emerge from this comparison as well as unique strategies that each species uses to cope with acid stress. We highlight some of the important research questions that still need to be addressed in this fascinating field.