In endochondral bone development chondrocytes undergo proliferation, hypertrophic differentiation, mineralization of the surrounding matrix, death, blood vessel invasion, and finally replacement of cartilage with bone. The chondrocytic growth plate is a unique mesenchymal tissue, as it is avascular but it requires blood vessel invasion in order to be replaced by bone. We have recently provided evidence that the growth plate is hypoxic during fetal development. Adaptation to hypoxia is a critical event in numerous pathological settings, such as tumor progression and survival of tissues in which blood flow has been suddenly interrupted. One of the hallmarks of the response to hypoxia is activation of the transcription factor HIF-1alpha. The von Hippel-Lindau (VHL) tumor suppressor protein is a component of a ubiquitin ligase promoting proteolysis of HIF-1alpha. By using a genetic approach, we have demonstrated that VHL and HIF-1alpha are critical regulators of endochondral bone development.