In aerobic organisms all cells have the capacity to respond to changes in oxygenation through the stabilisation and transcriptional activation of hypoxia inducible factor (HIF). At sites of tissue injury oxygen delivery to individual cells may be compromised or insufficient due to increased metabolic demands and it is to these areas that immune cells including neutrophils must migrate and operate effectively. In addition to the role of HIF to regulate the adaptive metabolic and survival responses of these cells at sites of reduced oxygenation, more complex interactions between HIF and pro-inflammatory pathways are now emerging. The mechanisms by which HIF modulates pro-inflammatory myeloid cell lifespan and function remain to be fully characterised but roles for the oxygen sensing hydroxylase enzymes through direct hydroxylation of nuclear factor-kappa B (NF-B) and its repressor protein IkBa have been suggested. The ability of HIF to modulate cellular glucose utilisation is also thought to be important, with the maintenance of intracellular ATP pools linked to enhanced myeloid cell aggregation, motility, invasiveness and bacterial killing. Additional non-hypoxia mediated routes to up-regulate HIF are also now recognised. In this review we describe the role of HIF in the oxygen sensing response, and the oxygen-dependent and -independent regulation of myeloid cell function and longevity. Understanding these processes and the role they play in regulating innate immune responses within inflamed sites, both hypoxic and normoxic, may offer new opportunities for therapeutic intervention.