Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to hypoxia are orchestrated in part through activation of the hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O(2)-sensitive signalling pathways have also been implicated: signalling through the mammalian target of rapamycin (mTOR) kinase and signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.