Lung development follows a stereotypic program orchestrated by key interactions among epithelial and mesenchymal tissues. Deviations from this developmental program can lead to pulmonary diseases including bronchopulmonary dysplasia and pulmonary hypertension. Significant efforts have been made to examine the cellular and molecular basis of the tissue interactions underlying these stereotypic developmental processes. Genetically engineered mouse models, lung organ culture, and advanced imaging techniques are a few of the tools that have expanded our understanding of the tissue interactions that drive lung development. Intimate crosstalk has been identified between the epithelium and mesenchyme, distinct mesenchymal tissues, and individual epithelial cells types. For interactions such as the epithelial–mesenchymal crosstalk regulating lung specification and branching morphogenesis, the key molecular players, FGF, BMP, WNT, and SHH, are well established. Additionally, VEGF regulation underlies the epithelial–endothelial crosstalk that coordinates airway branching with angiogenesis. Recent work also discovered a novel role for SHH in the epithelial-to-mesenchymal (EMT) transition of the mesothelium. In contrast, the molecular basis for the crosstalk between upper airway cartilage and smooth muscle is not yet known. In this review we examine current evidence of the tissue interactions and molecular crosstalk that underlie the stereotypic patterning of the developing lung and mediate injury repair. J. Cell. Biochem. 115: 1469–1477, 2014. © 2014 Wiley Periodicals, Inc.