The physiologic response to changes in cellular oxygen tension is ultimately governed by a heterodimeric transcription factor called hypoxia-inducible factor (HIF), which, in adaptation to compromised oxygen availability, transactivates a myriad of genes, including those responsible for de novo vascularization, production of oxygen-carrying red blood cells, and anaerobic metabolism. Accumulation of HIF is observed in most types of solid tumors and is frequently associated with poor prognosis and disease progression, underscoring the importance and relevance of HIF in cancer. The protein stability and, thereby, the activity of HIF are principally regulated by the von Hippel-Lindau (VHL) tumor suppressor-containing E3 ubiquitin ligase complex (ECV) that targets the catalytic subunit HIFalpha for oxygen-dependent ubiquitin-mediated destruction. Individuals who inherit germline VHL mutation develop VHL disease, which is characterized by the development of hypervascular tumors in multiple yet specific organs. This review will examine recent progress in our understanding of the molecular mechanisms governing the function of ECV and the significance of consequential regulation of HIF in oncogenesis.