At birth, the pulmonary circulation dilates in response to an increase in O₂ tension and nitric oxide (NO). Both pulmonary artery smooth muscle cells (PA SMC) and endothelial cells directly sense an acute increase in O₂ tension. In PA SMC, the capacity to respond to an acute increase in O₂ tension is developmentally regulated. In fetal PA SMC, the ion channel that determines resting membrane potential is the large-conductance calcium-sensitive K⁺ (KCa) channel. The signaling pathway that results in pulmonary artery smooth muscle (PA SMC) relaxation in response to an acute increase in O₂ tension includes an increase in cytosolic cGMP, cGMP dependent kinase-mediated release of calcium (Ca²⁺) sparks from ryanodine-sensitive intracellular stores, KCa activation and membrane hyperpolarization. With maturation, concomitant with loss of the capacity to respond to an acute increase in O₂ tension, the ion channel that determines PA SMC resting membrane potential changes to a voltage-sensitive K⁺ (Kv) channel, as KCa channel expression decreases, Kv 2.1 expression and the sensitivity to acute hypoxia increases. If the perinatal pulmonary circulation responds incompletely to vasodilator stimuli a syndrome termed persistent pulmonary hypertension of the newborn (PPHN) results. PPHN is characterized by severe central hypoxemia as blood shunts away from the lung via the ductus arteriosus and the patent foramen ovale. PPHN is a significant cause of neonatal morbidity and mortality. PPHN is associated with perinatal infection, bleeding, asphyxia, and intrauterine exposure to cyclooxygenase inhibitors. PA SMC oxygen sensing is compromised in an ovine model of PPHN, as an acute increase in oxygen tension has no effect on cytosolic calcium. PA SMC KCa channel expression is decreased, the ion channel that determines resting membrane potential changes to a Kv channel, and intracellular Ca²⁺ homeostasis is compromised. Recent data indicates that in PA SMC from fetal lambs with chronic intrauterine pulmonary hypertension, capacitative calcium entry is increased and the expression of transient receptor protein channel 6 is increased, providing evidence that augmented capacitative Ca²⁺ entry may play an etiologic role in PPHN. Further data indicates that chronic intrauterine pulmonary hypertension effects not only the physiologic, but the molecular response of fetal PA SMC to an acute increase in O₂. In control fetal PA SMC, sustained exposure to room air concentrations of O₂ tension decreases both KCa and voltage-operated calcium channel expression, while increasing cGMP-sensitive kinase I alpha (cGMP Kinase I α) expression. In contrast, in PA SMC derived from fetal lambs with chronic intrauterine pulmonary hypertension, the O₂-induced decreases in KCa and VOCC channel expression and the O₂ -induced increase in cGMP Kinase I α are blocked. Since chronic intrauterine pulmonary hypertension has a long-term effect on the molecular response to sustained normoxia, the fetal experience of the pulmonary circulation may inform the response of pulmonary circulation well into adulthood. Recent data from our laboratory suggests that the developmental regulation of hypoxic inducible factor-1 (HIF-1) genetic expression may render the fetal pulmonary circulation uniquely sensitive to an acute increase in O₂ tension. In specific, HIF-1 mRNA expression is increased by hypoxia in fetal, but not adult, PA SMC. Conversely, normoxia decreases HIF-1 expression in adult, but not fetal PA SMC. From a teleologic perspective, relatively robust expression of hypoxia-sensitive genes can be rationalized by recognition that mammalian survival is absolutely contingent upon the capacity of the pulmonary circulation to vasodilate at parturition in response to an acute increase in O₂ tension. Data indicating augmented HIF-1 mRNA and protein expression in the fetal, but not the adult, pulmonary circulation supports the notion that the low oxygen tension environment of the normal fetus increases expression of a transcription factor responsible for controlling expression of developmentally essential hypoxia-sensitive molecules. Fetal PAEC respond to acute normoxia with an increase in cytosolic calcium. The O₂-induced increase in cytosolic calcium results from membrane depolarization, entry of extracellular calcium, and release of calcium from inositol triphosphate-sensitive stores. Interestingly, in PAEC from fetal lambs with chronic intrauterine pulmonary hypertension, cytosolic calcium does not increase in response to an increase in oxygen tension. In PAEC derived from control fetal lambs nitric oxide production increases in response to acute normoxia. However, in animals with chronic intrauterine pulmonary hypertension, PAEC cytosolic nitric oxide production does not increase in response to acute normoxia.