Hypoxia-inducible factors (HIFs), specifically HIF1α and HIF2α, play critical roles in tumor growth and progression. While initially thought to have overlapping functions, recent studies reveal distinct and sometimes opposing activities of these factors in both normal physiology and disease. These differences are mediated through unique target genes and interactions with oncoproteins and tumor suppressors like MYC and p53. Understanding these roles is crucial as HIF inhibitors are being evaluated as potential cancer therapies. HIFs are heterodimers composed of an α subunit (HIF1α, HIF2α, or HIF3α) and a β subunit (HIF1β, also known as ARNT). Under hypoxia, HIFα subunits are stabilized, leading to increased transcriptional activity. This stabilization is primarily regulated by post-translational modifications, particularly by prolyl-hydroxylases (PHDs) and the Von Hippel-Lindau (VHL) tumor suppressor protein. HIF1α and HIF2α have distinct but overlapping functions. HIF1α is broadly expressed, while HIF2α is more restricted and abundant in blood vessels. HIF2α is involved in vascular endothelial cell function and has been linked to VEGF expression. Both HIF1α and HIF2α are co-expressed in many cell types, but their activities differ in response to hypoxia and oncogenic signals. HIF1α and HIF2α regulate different sets of genes, with HIF1α primarily involved in glycolytic pathways and HIF2α in genes related to cell proliferation and angiogenesis. They also interact with other proteins, such as MYC and p53, to influence tumor progression. HIF2α has been shown to promote tumor growth and progression, particularly in renal clear cell carcinomas (RCCs), where it is often overexpressed due to VHL loss. HIF1α and HIF2α also differ in their regulation at the transcriptional, translational, and stability levels. HIF1α is regulated by mTORC1 and mTORC2, while HIF2α is primarily mTORC2-dependent. Post-translational modifications, such as hydroxylation, acetylation, and phosphorylation, further modulate their activities. HIFs interact with oncogenes and tumor suppressors, influencing pathways like c-Myc, p53, and mTOR. HIF1α generally inhibits c-Myc and p53, while HIF2α promotes their activity. HIF2α also enhances mTORC1 activity, promoting cell proliferation. These interactions highlight the complex balance between HIF1α and HIF2α in tumor progression. HIF inhibitors are being explored as potential cancer therapies, as they can target the hypoxicHypoxia-inducible factors (HIFs), specifically HIF1α and HIF2α, play critical roles in tumor growth and progression. While initially thought to have overlapping functions, recent studies reveal distinct and sometimes opposing activities of these factors in both normal physiology and disease. These differences are mediated through unique target genes and interactions with oncoproteins and tumor suppressors like MYC and p53. Understanding these roles is crucial as HIF inhibitors are being evaluated as potential cancer therapies. HIFs are heterodimers composed of an α subunit (HIF1α, HIF2α, or HIF3α) and a β subunit (HIF1β, also known as ARNT). Under hypoxia, HIFα subunits are stabilized, leading to increased transcriptional activity. This stabilization is primarily regulated by post-translational modifications, particularly by prolyl-hydroxylases (PHDs) and the Von Hippel-Lindau (VHL) tumor suppressor protein. HIF1α and HIF2α have distinct but overlapping functions. HIF1α is broadly expressed, while HIF2α is more restricted and abundant in blood vessels. HIF2α is involved in vascular endothelial cell function and has been linked to VEGF expression. Both HIF1α and HIF2α are co-expressed in many cell types, but their activities differ in response to hypoxia and oncogenic signals. HIF1α and HIF2α regulate different sets of genes, with HIF1α primarily involved in glycolytic pathways and HIF2α in genes related to cell proliferation and angiogenesis. They also interact with other proteins, such as MYC and p53, to influence tumor progression. HIF2α has been shown to promote tumor growth and progression, particularly in renal clear cell carcinomas (RCCs), where it is often overexpressed due to VHL loss. HIF1α and HIF2α also differ in their regulation at the transcriptional, translational, and stability levels. HIF1α is regulated by mTORC1 and mTORC2, while HIF2α is primarily mTORC2-dependent. Post-translational modifications, such as hydroxylation, acetylation, and phosphorylation, further modulate their activities. HIFs interact with oncogenes and tumor suppressors, influencing pathways like c-Myc, p53, and mTOR. HIF1α generally inhibits c-Myc and p53, while HIF2α promotes their activity. HIF2α also enhances mTORC1 activity, promoting cell proliferation. These interactions highlight the complex balance between HIF1α and HIF2α in tumor progression. HIF inhibitors are being explored as potential cancer therapies, as they can target the hypoxic