Research in the field of oxygen sensing and metabolic adaptation to hypoxia is often focused on the acute response of cells to fluctuations in environmental oxygen availability. In order to mimick tissue hypoxia, cultured cells routinously grown at 21% oxygen in the gas phase are then subjected to oxygen concentrations of 3% or even less. However, such a drastic shift in oxygen concentrations is rather unphysiologic, as tissues in situ are dealing with a great variability of low pO2 values per se, even when the inspiratory pO2 is considered to be "normoxic". Therefore, we were interested to study changes in the response of the HIF-PHD oxygen sensing system in a tissue culture model of long term hypoxia, which would be a more suitable approximation to in vivo situations of tissue oxygenation. Using such a model system we demonstrated in a broad range of cell lines that HIF-1 activation indeed is a transient event and cells are capable to adapt to a given oxygen treshold by increasing the hydroxylation capacity of the oxygen sensors PHD2 and PHD3, thus establishing a new base-line, "steady state" activation of the HIF-PHD sensory circuit.