Moesin belongs to the ezrin/radixin/moesin (ERM) protein family and participates in cellular functions, such as morphogenesis and motility, by cross-linking between the actin cytoskeleton and plasma membranes. Although moesin seems necessary for tissue construction and repair, its function at the whole body level remains elusive, perhaps because of redundancy among ERM proteins. To determine the role played by moesin in the modulation of pulmonary alveolar structure associated with lung injury and repair, we examined the morphological changes in the lung and the effect of bleomycin-induced lung injury and fibrosis in moesin-deficient (Msn(-/Y)) and control wild-type mice (Msn(+/Y)). Immunohistochemical analysis revealed that moesin was specifically localized in the distal lung epithelium, where ezrin and radixin were faintly detectable in Msn(+/Y) mice. Compared with Msn(+/Y) mice, Msn(-/Y) mice displayed abnormalities of alveolar architecture and, when treated with bleomycin, developed more prominent lung injury and fibrosis and lower body weight and survival rate. Furthermore, Msn(-/Y) mice had abnormal cytokine and chemokine gene expression as shown by real-time PCR. This is the first report of a functional involvement of moesin in the regulation of lung inflammation and repair. Our observations show that moesin critically regulates the preservation of alveolar structure and lung homeostasis.