GPR64, also known as Adhesion G protein-coupled receptor G2 (ADGRG2) or Human Epididymis-specific protein 6 (HE6), is a member of the adhesion G protein-coupled receptor (aGPCR) family and is primarily recognized for its role in male fertility. It is predominantly expressed in the epididymis and parathyroid gland, where it helps maintain ion/pH homeostasis and is involved in sperm maturation and fluid reabsorption. Recent studies have also identified GPR64 in other tissues, such as gastrointestinal tuft cells, where it may play a role in chemosensory functions. Additionally, GPR64 has been implicated in various cancers, including endometrial cancer and Ewing sarcoma, where it may influence tumor growth and metastasis. Despite its diverse functions, the exact mechanisms of GPR64 signaling remain under investigation, with ongoing research aiming to optimize peptide ligands for better receptor characterization.