At the cellular level, oxygen partial pressure (pO2) is sensed by a family of protein hydroxylases. These enzymes transmit the information about the current pO2 directly to hypoxia-inducible transcription factors (HIFs) in the form of covalently attached hydroxy groups which regulate abundance and activity of the HIFs. In addition to this highly specific and direct mechanism of oxygen sensing, mitochondria were repeatedly proposed to sense oxygen and to transmit the signal in the form of a side product of the electron transport chain, i.e. the reactive oxygen species (ROS). However, the exact correlation between pO2 and ROS production, the precise downstream targets of ROS, and how ROS regulate these targets at the molecular level, are questions that remain unanswered. Supported by recent novel data, an alternative model is discussed which is based on the redirection of oxygen towards the protein hydroxylase oxygen sensors. Under conditions of changes in oxygen usage, e.g. following changes in mitochondrial function or cellular metabolism, oxygen redirection would provide an elegant explanation for HIF regulation under apparently constant external oxygen concentrations.