Vanilloid agonists (capsaicin, resiniferatoxin, [RTX]) applied to the peripheral nerves provide conduction blockade. In contrast to the analgesic component of conduction anesthesia produced by local anesthetics, vanilloid agonists provide conduction analgesia not associated with suppression of motor or sensory functions not related to pain. Vanilloid agonists provide conduction analgesia selectively because their effect on the nerve trunks is limited to C- and ADelta-fibers. RTX is much more potent than capsaicin and has a wider therapeutic window. In rat experiments, perineural RTX produced a long-lasting thermal and mechanical hypoalgesia with a very wide separation between effective concentrations (from 0.00003% to 0.001%) providing an effect lasting from several hours to several weeks. A nerve block with RTX prevented the development of thermal and mechanical hyperalgesia as well as pain behavior in a model of incisional pain. RTX-induced conduction blockade has an inherent drawback of TRPV1 agonists, the initial excitation (pain); therefore, a local anesthetic should be injected to prevent it. When RTX was applied to the rat's sciatic nerve in doses necessary to provide conduction analgesia, the frequency of unmyelinated fiber degeneration was more than an order of magnitude lower than that with the therapeutic concentration of lidocaine. These promising results should be confirmed by experiments in species other than rodents (pigs, sheep). Taken together, the data indicate possible clinical applicability of vanilloid-induced conduction analgesia.