With little in the way of effective therapeutic strategies to target the innate immune response, a better understanding of the critical pathways regulating neutrophil and macrophage responses in inflammation is key to the development of novel therapies. Hypoxia inducible factor (HIF) was originally identified as a central transcriptional regulator of cellular responses to oxygen deprivation. However, the HIF signalling pathway now appears, in myeloid cells at least, to be a master regulator of both immune cell function and survival. As such, understanding the biology of HIF and its regulators may provide new approaches to myeloid-specific therapies that are urgently needed.