The regulation of cellular metabolism, survival, and proliferation is contingent upon oxygen availability. Part of the mechanism by which cells react to oxygen levels is the transcriptional activity of hypoxia-inducible factors (HIFs). Throughout the tissue of solid tumors, there are frequently areas of hypoxia due to the disordered vascular architecture and necrotic areas. The hypoxic state varies both spatially and temporally in these areas. Diverse populations of tumor cells with varying tumor-initiating potentials or cancer cell “stemness” are frequently found in spontaneous tumors. Clonal heterogeneity can be linked to specific regions inside a tumor where distinct metastatic potential clones are found, indicating that the tumor microenvironment may play a major role in the development of distinct clonal populations. Recent studies have connected a tumor population known as cancer stem cells (CSCs), which resemble stem cells, to both the potential for metastasis and resistance to traditional therapies. It has been demonstrated by us and others that CSCs live in two niches found in brain tumors: the surrounding necrotic tissue and the perivascular area. Limitations in oxygen availability raise the proportion of CSCs and encourage the development of a stem-like state. HIFs have a crucial role in the survival, self-renewal, and tumor development of cancer stem cells. The regulation of cellular metabolism is significantly influenced by oxygen, and in hypoxic settings, metabolic switches are mediated by HIFs. It is obvious that hypoxia has the capacity to have a substantial impact on CSC maintenance and evolution. HIF-1α and HIF-2α may have a role in controlling how cells respond to hypoxia and become resistant to anticancer treatments. An overview of HIFs’ functions in CSCs is given in this review. Because HIF-1α and HIF-2α have strong prognostic and predictive value in the clinic, clinical trials for HIF inhibitors should be designed with personalized medicine in mind.