High-altitude pulmonary edema (HAPE) is a form of lung edema which occurs in otherwise healthy subjects, thereby allowing the study of underlying mechanisms of pulmonary edema in the absence of confounding factors. Exaggerated pulmonary hypertension is a hallmark of HAPE and is thought to play an important part in its pathogenesis. Pulmonary vascular endothelial dysfunction and augmented hypoxia-induced sympathetic activation may be underlying mechanisms contributing to exaggerated pulmonary vasoconstriction in HAPE. Recent observations by our group suggest, however, that pulmonary hypertension itself may not be sufficient to trigger HAPE. Based on studies in rats, indicating that perinatal exposure to hypoxia predisposes to exaggerated hypoxic pulmonary vasoconstriction in adulthood, we examined effects of high-altitude exposure on pulmonary-artery pressure in a group of young adults who had suffered from transient perinatal pulmonary hypertension. We found that these young adults had exaggerated pulmonary vasoconstriction of similar magnitude to that observed in HAPE-susceptible subjects. Surprisingly, however, none of the subjects developed lung edema. These findings strongly suggest that additional mechanisms are needed to trigger pulmonary edema at high-altitude. Observations in vitro, and in vivo suggest that a defect of the alveolar transepithelial sodium transport could act as a sensitizer to pulmonary edema. The aim of this article is to review very recent experimental evidence consistent with this concept. We will discuss data gathered in mice with targeted disruption of the gene of the alpha subunit of the amiloride-sensitive epithelial sodium channel (alpha ENaC), and present preliminary data on measurements of transepithelial sodium transport in vivo in HAPE-susceptible and HAPE-resistant mountaineers.