Airway mucus hypersecretion is a prominent feature of many obstructive lung diseases. We thus determined the ontogeny and exocytic phenotype of mouse airway mucous cells. In naive mice, ciliated (approximately 40%) and nonciliated (approximately 60%) epithelial cells line the airways, and > 95% of the nonciliated cells are Clara cells that contain Clara cell secretory protein (CCSP). Mucous cells comprise < 5% of the nonciliated cells. After sensitization and a single aerosol antigen challenge, alcian blue-periodic acid Schiff's positive mucous cell numbers increase dramatically, appearing 6 h after challenge (21% of nonciliated/nonbasal cells), peaking from Days 1-7 (99%), and persisting at Day 28 (65%). Throughout the induction and resolution of mucous metaplasia, ciliated and Clara cell numbers identified immunohistochemically change only slightly. Intracellular mucin content peaks at Day 7, and mucin expression is limited specifically to a Clara cell subset in airway generations 2-4 that continue to express CCSP. Functionally, Clara cells are secretory cells that express the regulated exocytic marker Rab3D and, in antigen-challenged mice, rapidly secrete mucin in response to inhaled ATP in a dose-dependent manner. Thus, Clara cells show great plasticity in structure and secretory products, yet have molecular and functional continuity in their identity as specialized apical secretory cells.