Vascular endothelial growth factors (VEGFs) are crucial regulators of vascular development and function in both health and disease. This review focuses on the signal transduction mechanisms of VEGF ligands and their receptors, which include three tyrosine kinase receptors (VEGFR1, VEGFR2, and VEGFR3) and coreceptors like neuropilins (NRPs) and integrins. The complex interactions between these components modulate the output of VEGF signaling. Therapeutics targeting VEGF signaling components have been developed to inhibit angiogenesis in diseases such as cancer. The review covers the current understanding of VEGF signal transduction, including receptor dimerization, tyrosine phosphorylation, and the involvement of NRPs and integrins. It also discusses the role of VEGF signaling in regulating angiogenesis, survival, permeability, and lymphatic function. The complex biology of VEGF signaling, including the influence of 3D context and the involvement of additional coreceptors, highlights the need for further research to fully understand and develop effective therapies.Vascular endothelial growth factors (VEGFs) are crucial regulators of vascular development and function in both health and disease. This review focuses on the signal transduction mechanisms of VEGF ligands and their receptors, which include three tyrosine kinase receptors (VEGFR1, VEGFR2, and VEGFR3) and coreceptors like neuropilins (NRPs) and integrins. The complex interactions between these components modulate the output of VEGF signaling. Therapeutics targeting VEGF signaling components have been developed to inhibit angiogenesis in diseases such as cancer. The review covers the current understanding of VEGF signal transduction, including receptor dimerization, tyrosine phosphorylation, and the involvement of NRPs and integrins. It also discusses the role of VEGF signaling in regulating angiogenesis, survival, permeability, and lymphatic function. The complex biology of VEGF signaling, including the influence of 3D context and the involvement of additional coreceptors, highlights the need for further research to fully understand and develop effective therapies.