Clara cell protein (CC16 or CC10) is a 15.8-kDa protein secreted all along the tracheobronchial tree and especially in the terminal bronchioles where Clara cells are localized. Even though the exact in vivo function of CC16 remains to be clarified, evidence is accumulating that CC16 plays an important protective role in the respiratory tract against oxidative stress and inflammatory response. CC16, however, presents also a major interest as a peripheral lung marker for assessing the cellular integrity or the permeability of the lung epithelium. The serum concentrations of CC16 are decreased in subjects with chronic lung damage caused by tobacco smoke and other air pollutants as a consequence of the destruction of Clara cells. By contrast, serum CC16 increases in acute or chronic lung disorders characterized by an increased airways permeability. The sensitivity of serum CC16 to an increased leakiness of the lung allows for the detection of defects of the epithelial barrier at ozone levels below current air-quality guidelines. Although the clinical significance of these early epithelial changes detected by serum CC16 remains to be determined, these results clearly show that the assay in serum of lung secretory proteins such as CC16 represents a new noninvasive approach to evaluate the integrity of the respiratory tract.