Rationale: Lung hypoplasia in congenital diaphragmatic hernia (CDH) appears to involve impaired alveolar septation. We hypothesized that disturbed deposition of elastin and expression of FGF18, an elastogenesis stimulus, occurs in CDH. Objectives: To document FGF18 and elastin in human CDH and ovine surgical and rat nitrofen models; to use models to evaluate the benefit of treatments. Methods: Human CDH and control lungs were collected post-mortem. Diaphragmatic hernia was created in sheep at 85d; fetal lungs were collected at 139d (term=145d). Pregnant rats received nitrofen at 12d; fetal lungs were collected at 21d (term=22d). Some of the sheep fetuses with hernia underwent tracheal occlusion (TO); some of the nitrofen-treated pregnant rats received vitamin A. Both treatments are known to promote lung growth. Main results: Coincidental with the onset of secondary septation, FGF18 protein increased 3-fold in control human lungs, which failed to occur in CDH. FGF18 labeling was found in interstitial cells of septa. Elastin staining demonstrated poor septation and markedly decreased elastin density in CDH lungs. Consistently, lung FGF18 transcripts were diminished 60% and 83% by CDH in sheep and rats, respectively, and elastin density and expression were also diminished. TO and vitamin A restored FGF18 and elastin expression in sheep and rats, respectively. TO restored elastin density. Conclusions: Impaired septation in CDH is associated with decreased FGF18 expression and elastic fiber deposition. Simultaneous correction of FGF18 and elastin defects by TO and vitamin A suggests that defective elastogenesis may result, at least partly, from FGF18 deficiency.