It is well recognized that human tumours are hypoxic compared to normal adjacent tissues and that hypoxia is related to a poor outcome regardless of modality of treatment, including surgery alone, radiotherapy or chemotherapy. Hypoxia regulates a complex programme of gene transcription via hypoxia‐inducible factors 1 and 2 (HIF‐1,‐2). We have shown that in breast cancer and many other tumour types, tumour‐associated macrophages express high levels of HIF‐2α compared to normal tissue macrophages and compared to the tumour. This high macrophage HIF‐2α is an independent prognostic factor for poor outcome. The mechanisms up‐regulating HIF‐2α in macrophages may include inflammatory cytokines as well as hypoxia. Differentiation of monocytes into macrophages increases the basal level of HIF‐2α protein and changes the programme of hypoxia. Many of these inducible genes are involved in inflammation and angiogenesis. Thus, the conversion of a peripheral monocyte into a macrophage generates a complex new programme of hypoxia‐responsive genes that may contribute to angiogenesis and the complex microenvironment within the tumour, and as such provides important targets for therapy.