The studies by Andrè et al. (4) and Bessac et al. (16) unequivocally establish the necessity of the gene product of the Trpa1 gene, the TRPA1 channel, for the response of airway sensory neurons to airborne irritants. However, based on this important step forward, it will be interesting to study pertinent follow-up questions regarding the signaling hierarchy, which, as we now know, contains Trpa1 gene products as one critical hub. For example, do airborne irritants activate TRPA1 directly or indirectly? As to the latter, this can possibly be achieved via other sensory neuron surface receptors or via interaction of the irritants with (lipid) components of the outer cell membrane. Moreover, what role do epithelial factors play in the activation of TRPA1-positive airway sensory neurons? In terms of intracellular signal transduction in these neurons, it will be interesting to learn how proteinase-activated receptors (PARs) and kinases sensitize (or desensitize) TRPA1, and what eventual roles store-operated Ca²⁺ entry (SOCE) and receptor-operated Ca²⁺ entry (ROCE) play in Ca²⁺ influx via TRPA1 (24). In the figure, the channel is depicted with its numerous N-terminal ankyrin-repeat domains (ARDs), which supposedly anchor the channel to the cytoskeleton; also illustrated is the channel’s pore-loop domain (highlighted in dark blue) between transmembrane (TM) domains 5 and 6. C, C-terminal; N, N-terminal. Adapted with permission from Cell (27).