Hypoxia is associated with a diverse range of physiological and pathophysiological processes, including development, wound healing, inflammation, vascular disease and cancer. The requirement that eukaryotic cells have for molecular oxygen as the terminal electron acceptor for the electron transport chain means that the maintenance of oxygen delivery is key for bioenergetic homeostasis. Metazoans have evolved an effective way to adapt to hypoxic stress at the molecular level through a transcription factor termed the hypoxia inducible factor. A family of oxygen-sensing hydroxylases utilizes molecular oxygen as a co-substrate for the hydroxylation of hypoxia inducible factor α subunits, thereby reducing its expression and transcriptional activity when oxygen is available. Recent studies have indicated that other hypoxia-responsive transcriptional pathways may also be hydroxylase-dependent. In this review, we will discuss the role of hydroxylases in the regulation of NF-κB, a key regulator of immunity and inflammation. Developing our understanding of the role of hydroxylases in hypoxic inflammation may identify novel therapeutic approaches in chronic inflammatory disease.