The vascular network delivers oxygen and nutrients to all cells in the body, and oxygen availability serves as a primary regulator of this complex organ. Hypoxia, or low oxygen levels, is a common phenomenon in both normal mammalian development and human disease. The hypoxia-inducible factors (HIFs) are transcription factors that mediate the response to low oxygen levels by regulating the expression of numerous angiogenic, metabolic, and cell cycle genes. HIF modulation has therapeutic potential for various pathologies, including cancer, ischemic heart disease, peripheral artery disease, wound healing, and neovascular eye diseases. HIFs consist of three oxygen-regulated α-subunits (HIF-1α, HIF-2α, and HIF-3α) and a constitutively expressed β-subunit (Arnt, Arnt2, or Arnt3). Under normoxic conditions, HIF-α subunits are hydroxylated by prolyl hydroxylase enzymes (PHDs), leading to their ubiquitination and degradation. In hypoxic conditions, PHD activity is attenuated, allowing HIF-α accumulation and nuclear translocation. There, HIF-α forms a complex with Arnt and binds to hypoxia response elements (HREs) in the promoters of target genes, activating their transcription. HIFs play a crucial role in both physiological and pathological angiogenesis. In embryonic development, HIFs coordinate the formation of the primitive vascular system and regulate sprouting angiogenesis. In tumors, HIFs promote angiogenesis and vascular maturation, contributing to tumor progression and metastasis. In ischemic diseases, such as peripheral artery disease and myocardial infarction, HIFs enhance angiogenesis and arteriogenesis to improve blood flow and tissue perfusion. Recent studies have identified several compounds that inhibit HIF activity, which could be used as anti-angiogenic therapies. However, these compounds often have significant side effects and require further development. Overall, understanding the complex regulation of HIFs and their role in angiogenesis is essential for developing effective therapeutic strategies.The vascular network delivers oxygen and nutrients to all cells in the body, and oxygen availability serves as a primary regulator of this complex organ. Hypoxia, or low oxygen levels, is a common phenomenon in both normal mammalian development and human disease. The hypoxia-inducible factors (HIFs) are transcription factors that mediate the response to low oxygen levels by regulating the expression of numerous angiogenic, metabolic, and cell cycle genes. HIF modulation has therapeutic potential for various pathologies, including cancer, ischemic heart disease, peripheral artery disease, wound healing, and neovascular eye diseases. HIFs consist of three oxygen-regulated α-subunits (HIF-1α, HIF-2α, and HIF-3α) and a constitutively expressed β-subunit (Arnt, Arnt2, or Arnt3). Under normoxic conditions, HIF-α subunits are hydroxylated by prolyl hydroxylase enzymes (PHDs), leading to their ubiquitination and degradation. In hypoxic conditions, PHD activity is attenuated, allowing HIF-α accumulation and nuclear translocation. There, HIF-α forms a complex with Arnt and binds to hypoxia response elements (HREs) in the promoters of target genes, activating their transcription. HIFs play a crucial role in both physiological and pathological angiogenesis. In embryonic development, HIFs coordinate the formation of the primitive vascular system and regulate sprouting angiogenesis. In tumors, HIFs promote angiogenesis and vascular maturation, contributing to tumor progression and metastasis. In ischemic diseases, such as peripheral artery disease and myocardial infarction, HIFs enhance angiogenesis and arteriogenesis to improve blood flow and tissue perfusion. Recent studies have identified several compounds that inhibit HIF activity, which could be used as anti-angiogenic therapies. However, these compounds often have significant side effects and require further development. Overall, understanding the complex regulation of HIFs and their role in angiogenesis is essential for developing effective therapeutic strategies.