Hypoxia, a condition characterized by low oxygen tension in tumors, plays a crucial role in cancer progression, angiogenesis, metastasis, and therapy resistance. Tumor hypoxia leads to dysfunctional vascularization, epithelial-to-mesenchymal transition (EMT), altered metabolism, and increased cell quiescence. The hypoxia-inducible factor (HIF) pathway, along with PI3K/ AKT/mTOR, MAPK, and NFκB pathways, is activated in response to hypoxia, contributing to these processes. HIF stabilization and activity are regulated by oxygen sensors and can be modulated by epigenetic changes and mutations. Hypoxia-induced EMT enhances cancer cell migration and invasion, while HIF-1α expression is associated with aggressive tumor phenotypes and poor prognosis. Targeting HIF and downstream pathways, such as CAIX and LOX, offers potential therapeutic strategies. Additionally, hypoxia affects the tumor microenvironment, influencing stromal and immune cells, and contributing to immune resistance. Understanding the role of hypoxia in cancer progression can lead to new therapeutic targets and improve patient outcomes.Hypoxia, a condition characterized by low oxygen tension in tumors, plays a crucial role in cancer progression, angiogenesis, metastasis, and therapy resistance. Tumor hypoxia leads to dysfunctional vascularization, epithelial-to-mesenchymal transition (EMT), altered metabolism, and increased cell quiescence. The hypoxia-inducible factor (HIF) pathway, along with PI3K/ AKT/mTOR, MAPK, and NFκB pathways, is activated in response to hypoxia, contributing to these processes. HIF stabilization and activity are regulated by oxygen sensors and can be modulated by epigenetic changes and mutations. Hypoxia-induced EMT enhances cancer cell migration and invasion, while HIF-1α expression is associated with aggressive tumor phenotypes and poor prognosis. Targeting HIF and downstream pathways, such as CAIX and LOX, offers potential therapeutic strategies. Additionally, hypoxia affects the tumor microenvironment, influencing stromal and immune cells, and contributing to immune resistance. Understanding the role of hypoxia in cancer progression can lead to new therapeutic targets and improve patient outcomes.