Hypoxia is a common physiologic and pathophysiologic stimulus which activates the expression of genes through oxygen-sensitive transcription factors including the hypoxia inducible factor (HIF) and nuclear factor-kappaB (NF-κB). Hypoxia-dependent gene expression can have important physiologic or pathophysiologic consequences for an organism depending upon the cause of the hypoxic insult. Consequently, this pathway represents an attractive therapeutic target in a number of disease states. While the mechanism linking hypoxia to the activation of HIF has been extensively studied, our understanding of how hypoxia activates NF-κB is limited. Recent studies have demonstrated that similar oxygen sensing mechanisms are employed in conferring oxygen sensitivity to both HIF and NF-κB-dependent gene expression. Furthermore, there is an extensive degree of cross-talk occurring between NF-κB and HIF. Investigations into mechanisms of hypoxic activation of HIF and NF-κB and how these signaling pathways interact will uncover new therapeutic modalities in a diverse range of disease states where hypoxia is a feature of the microenvironment including cancer, vascular disease and chronic inflammation.