In recent years, numerous studies have generated data supporting the hypothesis that extracellular adenosine 5′-triphosphate (ATP) plays a major role in obstructive airway diseases. Studies in animal models and human subjects have shown that increased amounts of extracellular ATP are found in the lungs of patients with COPD and asthma and that ATP has effects on multiple cell types in the lungs, resulting in increased inflammation, induction of bronchoconstriction, and cough. These effects of ATP are mediated by cell surface P2 purinergic receptors and involve other endogenous inflammatory agents. Recent clinical trials reported promising treatment with P2X3R antagonists for the alleviation of chronic cough. The purpose of this review was to describe these studies and outline some of the remaining questions, as well as the potential clinical implications, associated with the pharmacologic manipulation of ATP signaling in the lungs.