Oleocanthal, a major phenolic compound in extra-virgin olive oil with antiinflammatory properties, elicits an unusual oral pungency sensed almost exclusively in the throat. This contrasts with most other common oral irritants, such as cinnamaldehyde, capsaicin, and alcohol, which irritate mucus membranes throughout the oral cavity. Here, we show that this rare irritation pattern is a consequence of both the specificity of oleocanthal for a single sensory receptor and the anatomical restriction of this sensory receptor to the pharynx, within the oral cavity. We demonstrate, in vitro, that oleocanthal selectively activates the hTRPA1 channel in HEK 293 cells and that its ability to excite the trigeminal nervous system in rodents requires a functional TRPA1. Moreover, we similarly demonstrate that the over-the-counter analgesic, ibuprofen, which elicits the same restricted pharyngeal irritation as oleocanthal, also specifically excites rodent sensory neurons via TRPA1. Using human sensory psychophysical studies and immunohistochemical TRPA1 analyses of human oral and nasal tissues, we observe an overlap of the anatomical distribution of TRPA1 and the regions irritated by oleocanthal in humans. These results suggest that a TRPA1 (ANKTM1) gene product mediates the tissue sensitivity to oleocanthal within the oral cavity. Furthermore, we demonstrate that, despite the fact that oleocanthal possesses the classic electrophilic reactivity of many TRPA1 agonists, it does not use the previously identified activation mechanism via covalent cysteine modification. These findings provide an anatomical and molecular explanation for a distinct oral sensation that is elicited by oleocanthal and ibuprofen and that is commonly experienced around the world when consuming many extra-virgin olive oils.