Abstract: G protein-coupled receptors (GPCRs) represent the largest family of membrane proteins and are the target of approximately half of all therapeutic drugs. There are ~300 orphan GPCRs, which have great potential in drug development. G protein-coupled receptor 35 (GPR35), a rhodopsin-like orphan GPCR, is widely involved in immune regulation, gastrointestinal disorders, cardiovascular diseases, cancer, as well as other diseases, suggesting its great potential as a therapeutic target in a variety of diseases. However, the current research on GPR35 is insufficient, including the true endogenous ligand has not been confirmed, the molecular mechanism of its role in disease is not fully understood, and there is a lack of effective intervention strategies targeting GPR35. This article summarizes the deorphatization of GPR35, GPR35-related signaling pathways and their association with various diseases, in order to provide a reference for in-depth study of GPR35 in diseases and development of drugs targeting GPR35.