The cloned vanilloid (capsaicin) receptor subtype 1 (VR1) integrates multiple noxious stimuli on peripheral terminals of primary sensory neurons. The initial excitation of these neurons is followed by a lasting refractory state, traditionally termed desensitization, that has clear therapeutic potential. Capsaicin is used to relieve neuropathic pain, uremic pruritus, and bladder overactivity. The ultrapotent vanilloid resiniferatoxin, now in phase 2 clinical trials, has improved tolerability. A less recognized human exposure to high capsaicin concentrations may occur by pepper sprays used in law enforcement. Evidence is mounting that VR1 expression is not restricted to sensory neurons. From the olfactory bulb to the cerebellum, VR1-expressing neurons are present in a number of brain nuclei, where they might be activated by anandamide. VR1 presence also was demonstrated in nonneuronal tissues. These discoveries place VR1 in a much broader perspective than pain perception and enhance the potential for unforeseen side effects, especially following prolonged vanilloid therapy. The expression of VR1 is plastic and down-regulated during vanilloid therapy, which might have a pivotal role in desensitization. Good evidence suggests altered VR1 expression in various disease states. This recognition not only may provide novel insights into pathogenesis but also may prove useful in diagnosis.