In the 1980', vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF) was identified and shown to be a key regulator of endothelial cell proliferation and migration, and vascular permeability. The essential role of VEGF and of VEGF receptors (VEGFRs) for the development of the embryonic vascular system has been established via gene disruption studies. This article summarizes the fundamental contributions that have been made in the early days of angiogenesis research to define the involvement of VEGF/VEGFRs in the developing vasculature.