Airway epithelial basal cells are known to be critical for regenerating injured epithelium and maintaining tissue homeostasis. Recent evidence suggests that the alpha7 nicotinic acetylcholine receptor (nAChR), which is highly permeable to Ca(2+), is involved in lung morphogenesis. Here, we have investigated the potential role of the alpha7 nAChR in the regulation of airway epithelial basal cell proliferation and the differentiation of the human airway epithelium. In vivo during fetal development and in vitro during the regeneration of the human airway epithelium, alpha7 nAChR expression coincides with epithelium differentiation. Inactivating alpha7 nAChR function in vitro increases cell proliferation during the initial steps of the epithelium regeneration, leading to epithelial alterations such as basal cell hyperplasia and squamous metaplasia, remodeling observed in many bronchopulmonary diseases. The regeneration of the airway epithelium after injury in alpha7(-/-) mice is delayed and characterized by a transient hyperplasia of basal cells. Moreover, 1-year-old alpha7(-/-) mice more frequently present basal cells hyperplasia. Modulating nAChR function or expression shows that only alpha7 nAChR, as opposed to heteropentameric alpha(x)beta(y) nAChRs, controls the proliferation of human airway epithelial basal cells. These findings suggest that alpha7 nAChR is a key regulator of the plasticity of the human airway epithelium by controlling basal cell proliferation and differentiation pathway and is involved in airway remodeling during bronchopulmonary diseases.