Hypoxia induces angiogenesis, a process critical for tissue development and function. Hypoxia-inducible factors (HIFs) are key regulators of this process, controlling genes involved in angiogenesis, metabolism, and cell cycle. HIFs are highly conserved transcription factors that respond to oxygen levels, with HIF-1α, HIF-2α, and HIF-3α as the α-subunits and HIF-β (Arnt) as the β-subunit. HIFs are regulated by prolyl hydroxylases (PHDs), which hydroxylate HIF-α under normoxic conditions, leading to its degradation. Under hypoxia, PHD activity is inhibited, allowing HIF-α to accumulate and translocate to the nucleus, where it binds to Arnt and activates target genes, including vascular endothelial growth factor (VEGF), which promotes angiogenesis. HIFs play a crucial role in both physiological and pathological angiogenesis. In embryonic development, HIFs coordinate vascular development with metabolic demands. In diseases such as cancer, hypoxia and HIF activation promote tumor growth by inducing angiogenesis and enhancing tumor cell survival. HIFs also regulate vascular remodeling, vessel maturation, and the recruitment of vascular support cells. In tumor angiogenesis, HIF-1α and HIF-2α regulate pro-angiogenic genes, including VEGF, Ang-1, Ang-2, and Tie-2, which are essential for tumor growth and metastasis. HIF inhibition is a promising therapeutic strategy for cancer, as it can reduce tumor angiogenesis and growth. However, single-agent anti-angiogenic therapy may paradoxically promote tumor metastasis by inducing hypoxia and activating HIF pathways. Therefore, targeting multiple pro-angiogenic pathways is more effective. Several compounds, including 2-methoxyestradiol, digoxin, and doxorubicin, inhibit HIF activity and have shown potential in cancer therapy. However, many HIF inhibitors are not specific and may have significant side effects. HIFs also play a role in vascular diseases such as peripheral artery disease (PAD) and coronary artery disease. In PAD, HIF activation promotes angiogenesis and arteriogenesis, which are essential for restoring blood flow in ischemic tissues. In coronary artery disease, HIF activity is associated with the development of collateral vessels, which improve blood flow to the heart. HIF inhibition or activation can influence vascular remodeling and collateralization, offering potential therapeutic strategies for ischemic diseases. Overall, HIFs are critical regulators of angiogenesis and vascular function, with significant implications for both health and disease. Understanding HIF signaling and its regulation is essential for developing effective therapies for a wide range of conditions, including cancer, vascular diseases, and ischemic disorders.Hypoxia induces angiogenesis, a process critical for tissue development and function. Hypoxia-inducible factors (HIFs) are key regulators of this process, controlling genes involved in angiogenesis, metabolism, and cell cycle. HIFs are highly conserved transcription factors that respond to oxygen levels, with HIF-1α, HIF-2α, and HIF-3α as the α-subunits and HIF-β (Arnt) as the β-subunit. HIFs are regulated by prolyl hydroxylases (PHDs), which hydroxylate HIF-α under normoxic conditions, leading to its degradation. Under hypoxia, PHD activity is inhibited, allowing HIF-α to accumulate and translocate to the nucleus, where it binds to Arnt and activates target genes, including vascular endothelial growth factor (VEGF), which promotes angiogenesis. HIFs play a crucial role in both physiological and pathological angiogenesis. In embryonic development, HIFs coordinate vascular development with metabolic demands. In diseases such as cancer, hypoxia and HIF activation promote tumor growth by inducing angiogenesis and enhancing tumor cell survival. HIFs also regulate vascular remodeling, vessel maturation, and the recruitment of vascular support cells. In tumor angiogenesis, HIF-1α and HIF-2α regulate pro-angiogenic genes, including VEGF, Ang-1, Ang-2, and Tie-2, which are essential for tumor growth and metastasis. HIF inhibition is a promising therapeutic strategy for cancer, as it can reduce tumor angiogenesis and growth. However, single-agent anti-angiogenic therapy may paradoxically promote tumor metastasis by inducing hypoxia and activating HIF pathways. Therefore, targeting multiple pro-angiogenic pathways is more effective. Several compounds, including 2-methoxyestradiol, digoxin, and doxorubicin, inhibit HIF activity and have shown potential in cancer therapy. However, many HIF inhibitors are not specific and may have significant side effects. HIFs also play a role in vascular diseases such as peripheral artery disease (PAD) and coronary artery disease. In PAD, HIF activation promotes angiogenesis and arteriogenesis, which are essential for restoring blood flow in ischemic tissues. In coronary artery disease, HIF activity is associated with the development of collateral vessels, which improve blood flow to the heart. HIF inhibition or activation can influence vascular remodeling and collateralization, offering potential therapeutic strategies for ischemic diseases. Overall, HIFs are critical regulators of angiogenesis and vascular function, with significant implications for both health and disease. Understanding HIF signaling and its regulation is essential for developing effective therapies for a wide range of conditions, including cancer, vascular diseases, and ischemic disorders.