In aerobic organisms oxygen is a rate-limiting substrate for the efficient production of energy, and therefore they need to adjust their metabolism to the availability of oxygen. For this reason, eukaryotes and prokaryotes independently developed mechanisms to perceive oxygen availability and integrate this into developmental and growth programs. Despite their ability to produce oxygen in the presence of light, plants can experience low oxygen conditions when the oxygen diffusion from the environment cannot satisfy the demand set by metabolic rates. The oxygen-sensing mechanism recently identified in plants shares striking similarities with those previously described in animal cells. While in bacteria the different oxygen-sensing pathways reported involve protein dimerization and phosphorylation cascades, in plants and animals this function is mediated by oxygendependent proteolysis. The plant oxygen-sensing pathway is regulated via the oxygen-dependent branch of the N-end rule, which regulates the stability of the group VII of the Ethylene Response Factors, key activators of the anaerobic response. Additionally, constitutively expressed ERF-VII proteins, such as RAP2.12, are bound to the acyl-CoA-binding proteins (ACBPs) at the plasma membrane and protected from aerobic degradation. In hypoxia, RAP2.12 is released from the membrane and relocalizes into the nucleus, where it activates the molecular response to oxygen deficiency. Additional factors, indirectly affected by oxygen availability, have also been suggested to play roles in the fine tuning of oxygen sensing in plants.