In healthy nonsmokers, inhalation of one single puff of cigarette smoke immediately evoked airway irritation and cough, which were either prevented or markedly diminished after premedication with hexamethonium. Single-fiber recording experiments performed in anesthetized animals showed that both C fibers and rapidly adapting receptors in the lungs and airways were stimulated by inhalation of one breath of cigarette smoke. Application of nicotine evoked an inward current and triggered depolarization and action potentials in a concentration-dependent manner in a subset of isolated vagal pulmonary sensory neurons. Taken together, these studies showed that activation of the nicotinic acetylcholine receptors expressed on airway sensory nerves is mainly responsible for the acute airway irritation and cough reflex elicited by inhaled cigarette smoke. Chronic exposure to cigarette smoke consistently induces enhanced cough responses to various inhaled tussive agents in guinea pigs. The increased cough sensitivity involves primarily an elevated sensitivity of cough sensors and also an enhanced synaptic transmission of their afferent signals at the nucleus tractus solitaries. In contrast to the observations in animal studies, both enhanced and diminished cough sensitivities to tussive agents have been reported in chronic smokers. This discrepancy is probably related to the history of chronic smoking of the individual smokers and the severity of existing airway inflammation and dysfunction. Furthermore, several other factors possibly contributing to the regulation of cough receptor sensitivity in chronic smokers should also be considered.