Oxygen deprivation leading to hypoxia is a common feature of solid tumours. Under these conditions a signalling pathway involving a key oxygen-response regulator termed the hypoxia-inducible factor (HIF) is switched on. HIF is a transcription factor that, in hypoxia, drives the induction or repression of a myriad of genes controlling multiple cell functions such as angiogenesis, metabolism, invasion/metastasis and apoptosis/survival. Thus, the level of oxygen in a cell dictates the molecular response of cells through modulation of gene expression. Here we review the central role of HIF in cancer progression through the tumour response to hypoxia. Within this context the following aspects will be discussed: i) the mechanism by which oxygen deprivation inhibits two oxygen-sensor hydroxylases, thereby releasing the alpha subunit of HIF from programmed destruction by the ubiquitin-proteasome system and from a lock on its transcriptional activity; ii) the way in which the bi-transcriptional activity of HIF-alpha, which is regulated by the interplay between an oxygen-sensor attenuator and co-activators, determines the repertoire of gene expression; and iii) the role that HIF plays in tumour metabolism, in particular in glycolysis, and consequent acidification of the microenvironment, which influences both cell survival and cell death. Finally, the direct link of HIF to tumourigenesis and metastasis will be investigated and approaches for fighting tumour progression through a better understanding of HIF-mediated modulation of tumour metabolism and cell death will be considered.