The Na/K ATPase, or Na/K pump, is an enzyme converting chemical energy of ATP hydrolysis into the energy of electrochemical sodium and potassium gradient that is used to maintain cellular volume, pH and Ca2+ levels. Apart from maintaining the cellular Na+ and K+ concentrations, Na/K ATPase is involved in signal transduction including activation of mitogenic and proliferative signalling cascades. Changes in the Na/K ATPase activity have an impact on cellular metabolic and redox state, since it controls mitochondrial reactive oxygen species (ROS) levels and ATP utilisation rates. Na/K ATPase is known to be oxygen- and redoxsensitive. Alterations in the Na/K pump activity in response to hypoxia-reoxygenation or shifts in cellular and environmental redox state play an important role in pathological and adaptive responses of cells to hypoxia or ischemia. Despite intensive studies, the mechanisms involved in redox- and oxygen-induced regulation of the Na/K ATPase remain largely unknown. The present review focuses on the possible targets of action of oxygen, oxidants and reductants on the Na/K ATPase and mechanisms of oxygen- and redox-sensitivity of the enzyme at the molecular and cellular levels. Finally, we also consider factors involved in systemic responses to hypoxia that influence activity of the transporter as well as potential physiological and pathological outcome of such changes.