Angiogenesis, the formation of new networks of blood vessels, has essential roles in embryonic development, organ homeostasis and disease progression. Several signalling molecules, such as vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs), transforming growth factor (TGF)-β and angiopoietin-1 and 2, are known to be key regulators of blood vessel development and network patterning. Among these, the roles of VEGF-A and its receptors in vessel morphogenesis are understood best. VEGF-A signalling plays a crucial role in embryonic development through the regulation of angiogenesis. VEGF-A regulates most of the endothelial response, such as the proliferation and migration of endothelial cells (ECs), vascular permeability and the selection of tip and stalk cells. VEGF-A signalling also regulates organ homeostasis in adults. If an organ is exposed to severe injury, VEGF-A induces the release of paracrine factors from ECs, which increase the rate of regeneration of the organ. VEGF-A signalling also has an important role in the progression of angiogenesis-related diseases, especially cancer. Consequently, many agents that block VEGF-A have been developed and reported as useful tools for the inhibition of the growth and metastatic spread of tumours. Here, we summarize recent reports of the multiple functions of VEGF-A signalling during development, organ regeneration and tumour progression.