Tumour growth at primary or secondary extravasation sites leads to localised regions of reduced oxygen tension (hypoxia) in cells both within and surrounding the tumour. Although the angiogenic response of the tumour cell to hypoxia has been widely examined, the effect of hypoxia on other cell types within the tumour microenvironment is less clear. The endothelium is highly responsive to local hypoxia and regulates tumour cell dissemination and ultimately metastatic success through differential regulation of hypoxia-inducible transcription factors (HIFs). The endothelial response to hypoxia particularly mediates key processes that regulate tumour vascularisation and cancer progression, including proliferation, migration, adherence, and vascular permeability. This article describes current understanding of the HIF-mediated endothelial response to hypoxia during cancer progression. Endothelial HIF signalling regulates tumour growth and metastasis and is therefore an attractive putative target for treatments that inhibit cancer progression.