The N-end rule pathway regulates protein degradation, which depends on exposed N-terminal sequences in prokaryotes and eukaryotes. In plants, conserved and specific enzymes stimulate selective proteolysis. Although a number of developmental and growth phenotypes have been reported for mutants in the N-end rule, its function has remained unrelated to specific physiological pathways. The first report of the direct involvement of the N-end rule in stress responses focused on hypoxic signaling and how the oxygen-dependent oxidation of cystein promotes the N-end rule-mediated degradation of ethylene responsive factor (ERF)-VII proteins, the master regulators of anaerobic responses. It has been suggested that plants have evolved specific mechanisms to tune ERF-VII availability in the nucleus. In this review, we speculate that ERF-VII proteins are reversibly protected from degradation via membrane sequestration. The oxidative response in plants subjected to anoxic conditions suggests that reactive oxygen and nitrogen species (reactive oxygen species and reactive nitrogen species) may interact or interfere with the N-end rule pathway-mediated response to hypoxia.