An increase in pulmonary artery pressure is a common observation in adult mammals exposed to alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest to understanding pulmonary vascular homeostasis and developing new treatments for pulmonary hypertension. In particular, it would be helpful to discover the key molecules in the integrated vascular response to hypoxia to inform potential drug targets. One strategy is to take advantage of experiments of nature; specifically, to understand the molecular basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. This is the motivation for genetic studies in populations and animals adapted to life at high altitudes. To date, these studies highlight the importance of hypoxia-inducible factor 2α (HIF-2α), encoded by EPAS1, and prolyl hydroxylase domain-containing protein 2 (PHD), encoded by EGLN1, and support efforts to pharmacologically manipulate HIF-2 activity as a treatment for pulmonary hypertension.