Little is known of the mechanisms underlying the marked fall in pulmonary vascular resistance that occurs at birth, but changes in the expression of endothelial vasoactive and angiogenic factors during lung development might play a key role. Nitric oxide, endothelin-1, and vascular endothelial growth factor have critical effects on vascular tone and cell growth. Here, we investigated the protein expression of endothelial nitric oxide synthase, endothelin-1 and its receptors, and vascular endothelial growth factor in pulmonary necropsy samples from 14 fetuses of different gestational ages and from 5 infants. Expression of endothelin-1 and its receptor endothelin-A was strong and stable. In contrast, expression of the endothelin-B receptor was weak in early gestation, then increased markedly in mid-gestation and remained high thereafter. The expression of endothelial nitric oxide synthase and vascular endothelial growth factor fell markedly after mid-gestation and remained low thereafter. These data point to a discrepancy between maturational and functional changes in human pulmonary vascular structures. The weak perinatal expression of endothelial nitric oxide could suggest that other potent vasodilatory mediators are responsible for the marked vasodilation observed at birth.