Abstract The Earth is home to environments characterized by low pH, including the gastrointestinal tract of vertebrates and large areas of acidic soil. Most bacteria are neutralophiles, but can survive fluctuations in pH. Herein, we review how Escherichia, Salmonella, Helicobacter, Brucella, and other acid-resistant Gram-negative bacteria adapt to acidic environments. We discuss the constitutive and inducible defense mechanisms that promote survival, including proton-consuming or ammonia-producing processes, cellular remodeling affecting membranes and chaperones, and chemotaxis. We provide insights into how Gram-negative bacteria sense environmental acidity using membrane-integrated and cytosolic pH sensors. Finally, we address in more detail the powerful proton-consuming decarboxylase systems by examining the phylogeny of their regulatory components and their collective functionality in a population. The authors focus on the manifold adaptive responses of neutralophilic Gram-negative proteobacteria and the molecular mechanisms of sensing acid stress.