Abstract What is the nature of the oxygen sensor(s) and how do organisms sense variations in oxygen? A progressive rise of oxidative stress due to the altered reduction–oxidation (redox) homeostasis appears to be one of the hallmarks of the processes that regulate gene transcription. Dynamic changes in oxygen homeostasis and its close association with redox equilibrium, therefore, constitute a signaling mechanism for the expression/activation of oxygenes. This variation subsequently regulates the compartmentalization and functioning of HIF-1α and NF-κB. In addition, oxygen-evoked regulation of HIF-1α and NF-κB is closely coupled with intracellular redox state, such that modulating redox equilibrium affects their responsiveness at the molecular level (expression/transactivation). Interestingly, are these particular transcription factors potential oxygen sensors? The basic components of the intracellular oxidative/redox machinery and its crucial regulation of oxygen- and redox-sensitive transcription factors may help understand the network of oxygen sensing mechanisms and redox-related pathways.