The role of the epithelial adhesion ligand laminin 5 (LN5) in lung development has been poorly investigated. To determine its potential involvement in lung organogenesis, we used immunofluorescence microscopy to investigate the distribution of LN5 and its integrin (Int) receptors α₂β₁, α₃β₁, α₆β₁, and α₆β₄ during human fetal airway branching morphogenesis and respiratory epithelium differentiation. At the pseudoglandular and canalicular stages of airway development, LN5 and its constituent chains were localized in the basement membrane (BM) of the proximal respiratory tubules and in the cytoplasm of the epithelial cells forming the growing epithelial buds, which expressed Int α₂β₁, α₃β₁, and, transiently, α₆β₁. At the alveolar and adult stages, LN5 and its constituent chains were localized both in the BM of evolving and differentiated bronchioles and in the alveolar parenchyma. The bronchiolar epithelium markedly expressed Int α₂β₁ and α₃β₁, whereas the alveolar parenchyma strongly expressed Int α₂β₁, α₃β₁, and α₆β₁. Throughout fetal development and in the adult, LN5 and its constituent chains were detected both in the tracheal BM, regardless of the degree of epithelial differentiation, and in the cytoplasm of the cells at the invading front of the growing glandular ducts. Ultrastructural studies showed that nucleation of the hemidesmosomes (HDs) correlated with the differentiation of the tracheal epithelium. These results suggest that LN5 may play multiple roles during branching morphogenesis, by modulating proliferation and/or migration of the epithelial cells in the respiratory buds and by establishing branch points, through interaction initially with Int α₆β₁ and later with Int α₂β₁ and α₃β₁. We also propose that LN5 may regulate the differentiation of the tracheal epithelium by means of Int‐β₄, which governs HD nucleation. © 2002 Wiley‐Liss, Inc.