The activation of hypoxia-inducible factor-1 (HIF-1) has been recognized as the key event in adaptation to hypoxia. HIF-1 is a hetero-dimeric transcription factor complex composed of the O₂-labile a- and the constitutive a-subunit. Under hypoxic conditions HIF-a accumulates due to the lack of degradation, is translocated into the nucleus and after hetero-dimerization with the a-subunit binds to respective hypoxia response element in oxygen-regulated genes. Normoxic degradation of HIF-a depends on the activity of prolyl hydroxylases (PHDs). PHDs hydroxylate HIF-a depending on the PO₂ and mark HIF-a for proteasomal degradation. Under hypoxia HIF-a evades hydroxylation and accumulates. Recent advances in imaging subcellular three-dimensional distribution of HIF-a and interacting proteins by 2-photon-microscopy have provided first insights into localisation of the O₂ sensing process. Direct observation of the assembly the HIF-1 complex in living cells will further improve our understanding of cellular adaptation to hypoxia.