<p>G protein-coupled receptors (GPCRs) are necessary for bridging the extracellular environment and the intracellular milieu. G Protein-Coupled Receptor 68 (GPR68), also known as Ovarian cancer G-protein coupled receptor 1 (OGR1), is an orphan receptor that does not have a clearly identified ligand. An abundance of research conducted in recent years has progressively unveiled its structure and function. GPR68 possesses a unique structure that enables it to detect protons outside cells. This binding transmits a signal facilitated by its downstream effectors, which consist of pathways involving signaling molecules, such as phospholipase C and mitogen-activated protein kinase. Consequently, GPR68 is positioned in the nexus of diverse cellular reactions such as inflammation and hypoxia. Although the only disease GPR68 has been definitively associated with is amelogenesis imperfecta, it is extensively expressed, and its misexpression has been tied to various malignancies and illnesses. Present review provides a comprehensive analysis of the existing research on GPR68, aiming to highlight its key role in the crosstalk between tissue pH and cellular behavior. Specifically, our analysis emphasizes that, under normal circumstances, GPR68 plays an essential role in preserving and facilitating the homeostatic state of many tissues. However, in the context of cancer, the acidic conditions of the tumor microenvironment cause GPR68 to promote tumor development. In conclusion, this review highlights the potential of biochemical interventions targeting GPR68 to alleviate diseases linked to its dysfunction.</p>