Transient receptor potential (TRP) channels were first described in Drosophila, where photoreceptors carrying trp gene mutations exhibited a transient voltage response to continuous light (Cosens and Manning, 1969). Since that time the TRP channel family has grown to include at least 20 members. TRP channels exhibit a wide variety of functions: invertebrate phototransduction, responses to painful stimuli and to moderate temperature changes, regulation of intracellular calcium stores, receptor mediated excitation and modulation of the cell cycle. Despite the clear physiological importance of TRP channels, little is known about what regulates their function or about their structure. One type of TRP channel, TRPV1, is a polymodal receptor that integrates a number of painful stimuli. These stimuli include: noxious heat,,extracellular acidification, with a pKa of about 5.3, anandamide and other arachidonic acid metabolites and capsaicin, a pungent extract from plants in the Capsicum family (Rosenbaum and Simon, 2007). A combination of electrophysiological, molecular biology and biochemical techniques has allowed us to study the structural and functional properties of the TRPV1 channel and we have determined important regions for its function. For example, by constructing several TRPV1- channel mutants in which cysteine residues were substituted for other amino acids and by using cysteine-modifying compounds, we have found a single cysteine residue located at the second ankyrin repeat of the N-terminus (C157) of TRPV1, which is solely responsible for activation of this channel by allicin, a pungent compound found in plants such as onions and garlic (Salazar et al., 2008). We have also engineered a functional cysteineless-TRPV1 in which all 18 native cysteines were substituted for other amino acids and used it to perform experiments with cysteine-modifiers. These experiments have allowed us to locate the gate that controls ion fluxes through the TRPV1 channel to an intracellular region in the S6 transmembrane domain near residue Y671 as well as to identify a constriction in the pore (near residue L681), which impedes the passage of larger molecules to the pore (Salazar et al., 2009). More recently, we have identified a new endogenous bioactive lipid that functions as a direct agonist of TRPV1, lysophosphatidic acid, and we have shown that this lisyolipid binds to residue K710 in the proximal C-terminus of TRPV1 that results in an increase of the open probability of the channel (Nieto-Posadas et al., 2012). Although the field of TRP-channel study has observed important advances, further studies are still needed to fully comprehend how these proteins are gated.