Hypoxia is widely recognised as a key driving force for tumor angiogenesis by its induction of vascular endothelial growth factor (VEGF) and other direct-acting angiogenic factors. We describe the effect of hypoxia on gene expression and downstream angiogenic signalling; however, the angiogenic process is complex, and many other signalling pathways beyond VEGF are implicated in the formation of new vessels. These include extra-cellular signalling pathways such as the notch/delta, ephrin/Eph receptor, roundabout/slit, and netrin/UNC (uncoordinated) receptor families as well as intracellular proteins such as hedgehog and sprouty. The remarkable diversity in angiogenic signalling pathways provides many opportunities for therapeutic intervention, and anti-angiogenesis is currently a major area of oncology research.