Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors highly expressed in the lung that contribute to alveolar epithelial cell differentiation during embryogenesis and the modulation of pulmonary inflammation during disease. When RAGE is over-expressed throughout embryogenesis, severe lung hypoplasia ensues, culminating in perinatal lethality. However, possible mechanisms that lead to the disappearance of pulmonary tissue are unclear. A time course of lung organogenesis commencing at E12.5 demonstrated that increased RAGE expression primarily alters lung morphogenesis beginning at E16.5. TUNEL immunohistochemistry and immunoblotting for active caspase-3 confirm a shift toward apoptosis in lungs from RAGE over-expressing mice when compared to wild type controls. This observation supports previous work wherein electron microscopy identified cellular blebbing of alveolar epithelium in embryonic RAGE over-expressing mice. Assaying for NF-κB also revealed elevated nuclear translocation in lungs from transgenic mice compared to controls. An RT-PCR array for genes regulated by NF-κB demonstrated elevated expression of Fas ligand, suggesting increased activity of the Fas-mediated signal transduction pathway in which ligand-receptor interaction triggers cell death. These data provide evidence that RAGE expression must be tightly regulated during homeostatic organogenesis. Furthermore, additional elucidation of RAGE signaling potentially involved in cell cycle abnormalities may provide insight into the progression of RAGE-mediated lung diseases.