Vascular endothelial growth factors (VEGFs) are key regulators of vascular development and function in health and disease. They act through three receptor tyrosine kinases (VEGFR1, VEGFR2, VEGFR3) and coreceptors like neuropilins (NRPs) and integrins. Therapies targeting VEGF signaling are used to inhibit angiogenesis in diseases such as cancer. VEGF signaling is complex, involving multiple ligands, receptor variants, and coreceptors that modulate signaling outcomes. VEGFR1 is widely expressed but has limited kinase activity and plays a role in negative regulation of VEGFR2 and monocyte migration. VEGFR2 is the main VEGF receptor on endothelial cells and is essential for vascular development and angiogenesis. It binds VEGFA with high affinity and is involved in endothelial cell proliferation, migration, and vascular tube formation. VEGFR3 is critical for lymphatic development and is expressed in lymphatic endothelial cells. It forms heterodimers with VEGFR2 and is involved in lymphatic vessel function. NRPs, such as NRP1 and NRP2, modulate VEGF signaling by enhancing receptor interactions and signaling pathways. Integrins also play a role in VEGFR signaling by influencing receptor activation and trafficking. VEGFR signaling is regulated by internalization and endosomal signaling, which allows continued signaling even after receptor internalization. The complexity of VEGF signaling is further modulated by coreceptors and other signaling molecules, highlighting the need for further research to fully understand the mechanisms underlying VEGF signaling and its role in vascular and lymphatic biology.Vascular endothelial growth factors (VEGFs) are key regulators of vascular development and function in health and disease. They act through three receptor tyrosine kinases (VEGFR1, VEGFR2, VEGFR3) and coreceptors like neuropilins (NRPs) and integrins. Therapies targeting VEGF signaling are used to inhibit angiogenesis in diseases such as cancer. VEGF signaling is complex, involving multiple ligands, receptor variants, and coreceptors that modulate signaling outcomes. VEGFR1 is widely expressed but has limited kinase activity and plays a role in negative regulation of VEGFR2 and monocyte migration. VEGFR2 is the main VEGF receptor on endothelial cells and is essential for vascular development and angiogenesis. It binds VEGFA with high affinity and is involved in endothelial cell proliferation, migration, and vascular tube formation. VEGFR3 is critical for lymphatic development and is expressed in lymphatic endothelial cells. It forms heterodimers with VEGFR2 and is involved in lymphatic vessel function. NRPs, such as NRP1 and NRP2, modulate VEGF signaling by enhancing receptor interactions and signaling pathways. Integrins also play a role in VEGFR signaling by influencing receptor activation and trafficking. VEGFR signaling is regulated by internalization and endosomal signaling, which allows continued signaling even after receptor internalization. The complexity of VEGF signaling is further modulated by coreceptors and other signaling molecules, highlighting the need for further research to fully understand the mechanisms underlying VEGF signaling and its role in vascular and lymphatic biology.