Transforming growth factor-α (TGF-α), epidermal growth factor (EGF), and their common EGF receptor have been shown to be involved in cell proliferation and lung maturation. The aim of the study was to determine the site of production of TGF-α and EGF mRNA and the cellular distribution of TGF-α/EGF proteins and EGF receptor, in fetal human lung. By usingin situ hybridization with 35 S-labeled cDNA probes in frozen sections from eight lungs from fetuses ranging from 12 to 33 wk of gestation, TGF-α and EGF mRNA transcripts appeared to be confined to the mesenchymal cells and mainly found in the dense connective tissue along the pleura, bronchi, and large vessels, but undetected in bronchial epithelial cells. The streptavidin-biotin immunoperoxidase method, applied to paraffin-embedded specimens from 39 fetuses ranging from 10 to 41 wk, showed that TGF-α, EGF, and EGF receptor exhibited a similar cellular distribution during the whole period of gestation. They were detected in the undifferentiated cells of the airway surface epithelium, mesothelial cells, smooth muscle, and a few mesenchymal cells, as early as 10 wk. After 12 wk, the immunoreactivity was strong in the ciliated, secretory, and basal cells, and in growing glands along the large airways, but proved lower in the the distal airways. After 24 wk, the immunoreactivity remained in the airway epithelium, but was mainly localized in the apical domain of ciliated cells, in alveolar cells, and in the serous cells of the glands. The presence of TGF-α, EGF, and EGF receptor during the whole period of fetal lung development suggests that these factors are not only mitogenic, but can also be involved in epithelial maturation, through paracrine secretion, as most TGF-α and EGF mRNA transcripts are expressed in mesenchymal cells.