Oxygen is essential for eukaryotic life and is inextricably linked to the evolution of multicellular organisms. Proper cellular response to changes in oxygen tension during normal development or pathological processes, such as cardiovascular disease and cancer, is ultimately regulated by the transcription factor, hypoxia‐inducible factor (HIF). Over the past decade, unprecedented molecular insight has been gained into the mammalian oxygen‐sensing pathway involving the canonical oxygen‐dependent prolyl‐hydroxylase domain‐containing enzyme (PHD)–von Hippel‐Lindau tumour suppressor protein (pVHL) axis and its connection to cellular metabolism. Here we review recent notable advances in the field of hypoxia that have shaped a more complex model of HIF regulation and revealed unique roles of HIF in a diverse range of biological processes, including immunity, development and stem cell biology.