This review article explores the interplay between hypoxia-inducible factors (HIFs) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways in cancer. Hypoxia and oxidative stress are core hallmarks of solid tumors, and both conditions activate HIFs and NRF2, which play pivotal roles in tumor growth and progression. HIFs, including HIF-1α and HIF-2α, orchestrate the cellular hypoxic response by activating genes that increase oxygen supply and reduce expenditure. NRF2, on the other hand, activates genes involved in oxidant removal and adaptive cell survival under conditions of excess oxygen and oxidative stress. The complex interplay between hypoxia and oxidative stress within the tumor microenvironment adds another layer of complexity to the HIF and NRF2 signaling systems. The review highlights the dynamic changes and functions of these pathways in response to hypoxia and oxidative stress, emphasizing their implications in the tumor milieu. Additionally, it examines the intricate interplay between HIFs and NRF2, providing insights into the significance of these interactions for the development of novel cancer treatment strategies. The article discusses the adaptive response systems to variable oxygen tensions, the regulation of HIFs and NRF2, and their cross-response in hypoxia and oxidative stress conditions. It also reviews the elevated expression of HIFs and NRF2 in cancer, their roles in cancer proliferation, survival, therapeutic resistance, angiogenesis, EMT/metastasis, and cancer stem cell (CSC) traits. The review concludes by discussing the cooperative effects of HIFs and NRF2 on core cancer phenotypes and the potential for targeting these pathways in cancer therapy.This review article explores the interplay between hypoxia-inducible factors (HIFs) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways in cancer. Hypoxia and oxidative stress are core hallmarks of solid tumors, and both conditions activate HIFs and NRF2, which play pivotal roles in tumor growth and progression. HIFs, including HIF-1α and HIF-2α, orchestrate the cellular hypoxic response by activating genes that increase oxygen supply and reduce expenditure. NRF2, on the other hand, activates genes involved in oxidant removal and adaptive cell survival under conditions of excess oxygen and oxidative stress. The complex interplay between hypoxia and oxidative stress within the tumor microenvironment adds another layer of complexity to the HIF and NRF2 signaling systems. The review highlights the dynamic changes and functions of these pathways in response to hypoxia and oxidative stress, emphasizing their implications in the tumor milieu. Additionally, it examines the intricate interplay between HIFs and NRF2, providing insights into the significance of these interactions for the development of novel cancer treatment strategies. The article discusses the adaptive response systems to variable oxygen tensions, the regulation of HIFs and NRF2, and their cross-response in hypoxia and oxidative stress conditions. It also reviews the elevated expression of HIFs and NRF2 in cancer, their roles in cancer proliferation, survival, therapeutic resistance, angiogenesis, EMT/metastasis, and cancer stem cell (CSC) traits. The review concludes by discussing the cooperative effects of HIFs and NRF2 on core cancer phenotypes and the potential for targeting these pathways in cancer therapy.