Local acidification is a common feature of many disease processes such as inflammation, infarction, or solid tumor growth. Acidic pH is not merely a sequela of disease but contributes to recruitment and regulation of immune cells, modifies metabolism of parenchymal, immune and tumor cells, modulates fibrosis, vascular permeability, oxygen availability, and consumption, invasiveness of tumor cells, and impacts on cell survival. Thus, multiple pH-sensing mechanisms must exist in cells involved in these processes. These pH sensors play important roles in normal physiology and pathophysiology, and hence might be attractive targets for pharmacological interventions. Among the pH-sensing mechanisms, OGR1 ( GPR68), GPR4 ( GPR4), and TDAG8 ( GPR65) have emerged as important molecules. These G protein-coupled receptors are widely expressed, upregulated in inflammation and tumors, sense changes in extracellular pH in the range between pH 8 and 6, and are involved in modulating key processes in inflammation, tumor biology, and fibrosis. This review discusses key features of these receptors and highlights important disease states and pathways affected by their activity.