In this review, we explore unique mechanisms of pheochromocytoma and paraganglioma initiation and management by drawing from recent examples involving rare mutations of hypoxia-related genes VHL, EPAS1 and SDHB, and of a poorly known susceptibility gene, TMEM127. These models expand our ability to predict variant pathogenicity, inform new functional domains, recognize environmental-gene connections, and highlight persistent therapeutic challenges for tumors with aggressive behavior. Here, EPAS1 is linked to pheochromocytoma.