Capsaicin in chili peppers bestows the sensation of spiciness.Since the discovery of its receptor,transient receptor potential vanilloid 1 (TRPV1) ion channel,how capsaicin activates this channel has been under extensive investigation using a variety of experimental techniques including mutagenesis,patch-clamp recording,crystallography,cryo-electron microscopy,computational docking and molecular dynamic simulation.A framework of how capsaicin binds and activates TRPV1 has started to merge:capsaicin binds to a pocket formed by the channel’s transmembrane segments,where it takes a tail-up,head-down configuration.Binding is mediated by both hydrogen bonds and van der Waals interactions.Upon binding,capsaicin stabilizes the open state of TRPV1 by pull-and-contact with the S4-S5 linker.Understanding the ligand-host interaction will greatly facilitate pharmaceutical efforts to develop novel analgesics targeting TRPV1.