Platelet-derived growth factors and their receptors (PDGF/PDGFRs) represent one of the most intensively studied families of growth factors in the last four decades. PDGF signaling plays an essential role in cell proliferation, differentiation, migration, and survival. In vivo studies documented an important role of PDGF signaling in normal development of several organs, such as the kidney, eye, or lung. Here, PDGF signaling is essential for the formation of intact mesenchymal cells during embryogenesis. Recently, this knowledge has been extended to a role of PDGF signaling in diseases in general, such as cancer and atherosclerosis, and more importantly in lung diseases, including PAH, lung cancer, and lung fibrosis. In this review, we provide an up-to-date overview of PDGF signaling, including tissue- and cell-type specific expression patterns and effects. We will highlight current therapeutic approaches modifying PDGF signaling in lung diseases and summarize clinical trials, in which PDGF signaling has been inhibited. In conclusion, while PDGF inhibition is currently used in multiple clinical trials, we suggest that more elaborate and specific approaches for spatio-temporal control of PDGF signaling are required for developing personalized approaches involving PDGF signaling in lung disease.