TRPA1 are calcium permeable, non-selective cation channels expressed in somatic and visceral nociceptors and many non-neuronal cells, including fibroblasts, odontoblasts, endothelial and glial cells. These channels are rapidly emerging as critical participants in the biological response to physical stimuli (temperature and pressure) and natural and synthetic environmental irritants, including many reactive electrophiles, oxidants and inflammatory mediators. Abnormal activation of TRPA1 has been linked to the pathogenesis of neuropathic pain, itch, atopic dermatitis, headache and asthma. Moreover, these channels are activated by clinically relevant drugs (e.g. dihydropyridines, chloroquine, clotrimazole, phenytoin) and this activation may result in unwanted side effects, but could also serve as a useful chemical template for the design of novel activators. The activation of TRPA1 by temperature has been controversial but evidence for its role in noxious thermosensation has gained significant weight since its description as a noxious cold sensor in 2003 by Patapoutian and colleagues (1). Recently, we uncovered a novel role of TRPA1 channels as sensors of lipopolysaccharide (LPS) (2), a toxic Gram-negative bacterial product, leading to pain and neurogenic inflammation. The ancient nature of LPS and the observation of a conserved role of TRPA1 in chemical avoidance underscore the evolutionary significance of this alert mechanism in animals.