Oxygen plays a pivotal role in the maintenance of life for all eukaryotes, with the exception of strict anaerobes. Eukaryotes have developed mechanisms to sense and respond to decreased oxygen levels. How eukaryotes sense oxygen is still not fully understood. What is (or are) the oxygen sensor(s)? This question has vital physiological and pathophysiological implications, because all living aerobic organisms have adaptive mechanisms to maintain oxygen homeostasis. A recent report describes a novel eukaryotic oxygen-sensing mechanism in the fission yeast Schizosaccharomyces pombe, involving the depletion of sterols as a trigger to induce gene expression in response to decreased oxygen levels. It is not yet clear whether this mechanism is involved in the mammalian response to hypoxia, possibly in conjunction with activation of one or both of the hypoxia-inducible factor (HIF-1 or HIF-2) transcription factors.