Reduced oxygen availability or increased demand for oxygen in cells leads to a stress condition known as hypoxia. Hypoxia is a physiological stimulus but is mostly known for its pathological consequences in cells and tissues. Given the importance of oxygen for cell viability and function, mechanisms of response and adaptation to hypoxia have evolved in all multicellular organisms. In mammalians, hypoxia induces a transcriptional response mediated by HIFs, and also other transcription factors, such as NF-κB. NF-κB is a complex family of transcription factors, known for being associated with immune responses and other stress responses in mammalians. Our recent study has revealed the importance of NF-κB for the hypoxia-induced transcriptional response of cells. NF-κB is needed for 30% of induced genes and for over 60% of gene repression observed in response to hypoxia. This mini review will focus on how hypoxia controls NF-κB and how NF-κB contributes to the response of cells in hypoxia. It also highlights areas where knowledge gaps still exist and where new directions for research should focus.