The Transient Receptor Potential Ankyrin TRPA channels are Ca2+-permeable non-selective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the N-terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This include a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel, and many other chemically-unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen and carbonyl species. TRPA1 is involved in acute and chronic pain, inflammation, plays a role in the pathophysiology of nearly all organ systems and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties and complex regulation to its roles in multiple pathophysiological conditions.