The article provides a comprehensive overview of the molecular mechanisms and clinical applications of angiogenesis, the process by which blood vessels grow and form. It highlights the significant progress made in understanding the molecular pathways involved in angiogenesis, particularly the role of vascular endothelial growth factor (VEGF) and its receptors. The authors discuss the clinical success of anti-angiogenic drugs in treating cancer and eye diseases, but also address the challenges and limitations, such as resistance and limited efficacy. They explore recent preclinical and clinical studies that have identified new molecular targets and principles, which may improve the therapeutic benefits of anti-angiogenic strategies. The article delves into the sequential steps of vessel branching, maturation, and quiescence, and the key molecular players involved. It also examines the VEGF family, including VEGF, VEGF-C, and PIGF, and their roles in angiogenesis. Additionally, the article discusses other growth factor families like PDGF, TGF-β, and FGF, and their contributions to vessel formation and maturation. The role of integrins, proteases, junctional molecules, chemokines, and G-protein-coupled receptors in angiogenesis is also covered. Finally, the authors address the refractoriness to VEGF blockade in advanced cancer, the challenges in adjuvant settings, and the potential of tumor vessel normalization as a future therapeutic target.The article provides a comprehensive overview of the molecular mechanisms and clinical applications of angiogenesis, the process by which blood vessels grow and form. It highlights the significant progress made in understanding the molecular pathways involved in angiogenesis, particularly the role of vascular endothelial growth factor (VEGF) and its receptors. The authors discuss the clinical success of anti-angiogenic drugs in treating cancer and eye diseases, but also address the challenges and limitations, such as resistance and limited efficacy. They explore recent preclinical and clinical studies that have identified new molecular targets and principles, which may improve the therapeutic benefits of anti-angiogenic strategies. The article delves into the sequential steps of vessel branching, maturation, and quiescence, and the key molecular players involved. It also examines the VEGF family, including VEGF, VEGF-C, and PIGF, and their roles in angiogenesis. Additionally, the article discusses other growth factor families like PDGF, TGF-β, and FGF, and their contributions to vessel formation and maturation. The role of integrins, proteases, junctional molecules, chemokines, and G-protein-coupled receptors in angiogenesis is also covered. Finally, the authors address the refractoriness to VEGF blockade in advanced cancer, the challenges in adjuvant settings, and the potential of tumor vessel normalization as a future therapeutic target.