This review provides the theoretical background of phenotypic and gene-based changes in the vessel wall triggered by acute hypoxia. Only in the last few decades has the endothelium been ascribed a prominent role as a modulator of vascular homeostasis under both physiological and pathological conditions. Molecular mechanisms leading to endothelial activation are being rapidly elucidated and their contribution to vascular dysfunction during hypoxia becoming better understood. New insights gained from hypoxic cell culture and ischaemic organ models may ultimately lead to new treatment strategies. If nothing else, insights gained from vascular research will lead to a more complete understanding of the inflammatory processes in blood vessels and how they impact on human disease.