Decreased oxygen availability is a common feature during embryonic development as well of malignant tumours. Hypoxia regulates many transcription factors, and one of the most studied is the hypoxia-inducible factor (HIF). As a consequence of HIF stabilisation, the cell constitutively upregulates the hypoxic programme resulting in the expression of genes responsible for global changes in cell proliferation, angiogenesis, metastasis, invasion, de-differentiation and energy metabolism. Of the three known alpha subunits of HIF transcription factors, HIF-1alpha and HIF-2alpha have been the most studied. Their differential expression and function have been widely discussed, however no clear picture has been drawn on how these two transcription factors differently regulate common and unique target genes. Their role as oncogenes has also been suggested in several studies. In this review we provide an overview of the current knowledge on some of the most important aspects of HIFalpha regulation, its role in tumour angiogenesis and energetic metabolism. We also give an overview of how the modulation of HIF regulating pathways is a potential therapeutic target that may have benefits in the treatment of cancer.