Transient receptor potential vanilloid 1 (TRPV1) channel, belonging to transient receptor potential (TRP) channel superfamily, is a ligand gated non-selective cation channel which can be activated by multiple physical and chemical stimuli. The abnormal irritation and expression of TRPV1 is involved in pathogenesis of various diseases, so that TRPV1 channel is one of the important targets for drug research and development. For a long time, TRPV1 channel has attracted much attention because of the excellent analgesic effect of TRPV1 modulators. Due to the recognition of the research work of receptors for temperature and touch by the 2021 Nobel Prize in physiology or medicine, TRPV1 channel has become the focus of attention once again. It has been more than 20 years of the research for TRPV1, but the gating mechanism and drug development are still the difficulties. TRPV1 agonists can only be used for topical administration, and the antagonists could be used for oral administration. However, the problem with antagonists is that they cause hyperthermia and damage to noxious heat detection, which is the result of TRPV1 antagonists simultaneously affecting capsaicin, H⁺ and heat gating. Studies have shown that there are common processes of the three gating mechanisms, but no way to affect a single gating mechanism. From the angles of physiological function, gating mechanism and drug discovery, this paper reviews the distribution and expression, functions and features as well as structural characteristics of TRPV1 channel. This paper focuses on three gating mechanisms and the progress of TRPV1 modulators in drug discovery. TRPV1 modulators are a exceptional analgesia drug, and have been studied in cardiovascular diseases, itch, cough, psychiatric disorders and diabetes. With the emerging of artificial intelligence (AI)-assisted drug design and the continuous exploration of gating mechanism, we should have confidence in the future of TRPV1 modulators.