Adaptive responses to hypoxia are essential for the survival of all organisms. Under hypoxic conditions, transcription of a large group of genes relevant for oxygen homeostasis is induced by the hypoxia-inducible factor-1 (HIF-1). These genes encode proteins that enable the cells to adapt to limiting oxygen levels by increasing oxygen delivery through induction of angiogenesis or erythropoiesis and producing ATP under anaerobic conditions. The stability of HIF-1alpha protein is also target of O2 regulation. At normoxia HIF-1alpha is hydroxylated at specific proline residues by a recently identified family of prolyl hydroxylases. Hydroxylated HIF-1alpha is recognized by the Von Hippel-Lindau tumor suppressor gene product (pVHL) as an ubiquitylation substrate that leads to proteasomal-dependent degradation of HIF-1alpha. We have recently demonstrated that the major subcellular compartment where degradation of HIF-1alpha occurs is dependent on the levels of proteasomal activity and on the localization of HIF-1alpha. Furthermore we have shown that the localization of HIF-1alpha degradation is a cell type-characteristic parameter. These observations indicate new levels of complexity in the regulation of HIF-1alpha degradation.