One of the functions of the mammalian hypoxic response in development and cancer is the generation of nascent vascular networks through angiogenesis. Through transcriptional regulation of the vascular endothelial growth factor A (VEGF-A) and other angiogenic factors, the Hypoxia-Inducible Factors can increase angiogenesis in an oxygen dependent fashion, and gives a survival and growth advantage to HIF wild type tumors. However, their role in other cell types is not always redundant. We are starting to understand that each cell type within the tumor microenvironment has specific hypoxia response strategies that independently affect tumor growth and tumor dispersion. We use genetic techniques to identify the role of hypoxia-triggered and HIF-dependent responses in different cell types, with a particular focus on cancer.