SUMMARYPlant cysteine oxidases (PCOs) are plant O2‐sensing enzymes. They catalyse the O2‐dependent step which initiates the proteasomal degradation of Group VII ethylene response transcription factors (ERF‐VIIs) via the N‐degron pathway. When submerged, plants experience a reduction in O2 availability; PCO activity therefore decreases and the consequent ERF‐VII stabilisation leads to upregulation of hypoxia‐responsive genes which enable adaptation to low O2 conditions. Resulting adaptations include entering an anaerobic quiescent state to maintain energy reserves and rapid growth to escape floodwater and allow O2 transport to submerged tissues. Stabilisation of ERF‐VIIs has been linked to improved survival post‐submergence in Arabidopsis, rice (Oryza sativa) and barley (Hordeum vulgare). Due to climate change and increasing flooding events, there is an interest in manipulating the PCO/ERF‐VII interaction as a method of improving yields in flood‐intolerant crops. An effective way of achieving this may be through PCO inhibition; however, complete ablation of PCO activity is detrimental to growth and phenotype, likely due to other PCO‐mediated roles. Targeting PCOs will therefore require either temporary chemical inhibition or careful engineering of the enzyme structure to manipulate their O2 sensitivity and/or substrate specificity. Sufficient PCO structural and functional information should make this possible, given the potential to engineer site‐directed mutagenesis in vivo using CRISPR‐mediated base editing. Here, we discuss the knowledge still required for rational manipulation of PCOs to achieve ERF‐VII stabilisation without a yield penalty. We also take inspiration from the biocatalysis field to consider how enzyme engineering could be accelerated as a wider strategy to improve plant stress tolerance and productivity.