An adequate supply with oxygen is essential for aerobic life. Oxygen serves as primary electron acceptor in many cellular reactions and is central for ATP generation in the mitochondria, making a tight adaptation of physiological functions to oxygen supply mandatory. Thereby, molecular oxygen, reactive oxygen species (ROS), and redox equivalents can serve as signalling molecules to monitor disruption of oxygen homeostasis and initiate adaptive processes. Key players in oxygen homeostasis are a family of hypoxia-inducible transcription factors (HIF) which control a variety of cellular adaptive processes in response to hypoxia. These transcription factors also play an increasingly important role in the cardiovascular response to multiple stress factors independently of hypoxia including vasoactive substances, thrombotic factors, inflammatory mediators and growth factors. Their ability to be regulated by ROS and metabolic alterations under these conditions make them true redox-sensitive transcription factors. In that regard it is not surprising that expression and function of NADPH oxidases, which serve as important sources of cardiovascular ROS in a variety of physiological and pathophysiological settings, are tightly connected to the HIF system and vice versa, culminating in the findings that some NADPH oxidases are direct HIF target genes. Interestingly, increasing evidence suggests that NADPH oxidases are also involved in the adaptation to hypoxia. Dissecting the mechanisms controlling the ROS-HIF axis in cardiovascular physiology and pathophysiology appears to be a promising strategy to understand the importance of redox signaling in cardiovascular function and to delineate novel therapeutic options for a variety of cardiovascular disorders.