The article discusses the importance of angiogenesis in cancer and other diseases, highlighting the dysregulation of this process in various pathologies, particularly cancer. The abnormal vascular network in tumors, characterized by dilated, tortuous, and hyperpermeable vessels, leads to spatial and temporal heterogeneity in blood flow and oxygenation, increased interstitial fluid pressure, and reduced efficacy of chemotherapy, radiotherapy, and immunotherapy. The discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis has led to the development of anti-VEGF therapeutics, which aim to inhibit VEGF activity and starve tumors. However, clinical trials of anti-VEGF monotherapy have been largely negative. Interestingly, combining anti-VEGF therapy with conventional chemotherapy has shown improved survival in cancer patients compared to chemotherapy alone. This paradox can be explained by the "vascular normalization" hypothesis, which suggests that anti-VEGF therapy changes the tumor vasculature towards a more mature or normal phenotype, reducing hyperpermeability, increasing vascular pericyte coverage, and improving basement membrane structure. These changes can lead to a more normal metabolic profile of the tumor microenvironment, enhanced delivery and efficacy of exogenously administered therapeutics, and improved radiotherapy and immune cell efficacy. The article also reviews the molecular and genetic regulators of vascular normalization, including proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFRβ, RGS5, Ang1/2, TGF-β). Finally, it discusses the implications of vascular normalization for the treatment of various diseases associated with abnormal angiogenesis.The article discusses the importance of angiogenesis in cancer and other diseases, highlighting the dysregulation of this process in various pathologies, particularly cancer. The abnormal vascular network in tumors, characterized by dilated, tortuous, and hyperpermeable vessels, leads to spatial and temporal heterogeneity in blood flow and oxygenation, increased interstitial fluid pressure, and reduced efficacy of chemotherapy, radiotherapy, and immunotherapy. The discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis has led to the development of anti-VEGF therapeutics, which aim to inhibit VEGF activity and starve tumors. However, clinical trials of anti-VEGF monotherapy have been largely negative. Interestingly, combining anti-VEGF therapy with conventional chemotherapy has shown improved survival in cancer patients compared to chemotherapy alone. This paradox can be explained by the "vascular normalization" hypothesis, which suggests that anti-VEGF therapy changes the tumor vasculature towards a more mature or normal phenotype, reducing hyperpermeability, increasing vascular pericyte coverage, and improving basement membrane structure. These changes can lead to a more normal metabolic profile of the tumor microenvironment, enhanced delivery and efficacy of exogenously administered therapeutics, and improved radiotherapy and immune cell efficacy. The article also reviews the molecular and genetic regulators of vascular normalization, including proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFRβ, RGS5, Ang1/2, TGF-β). Finally, it discusses the implications of vascular normalization for the treatment of various diseases associated with abnormal angiogenesis.