Cancer stem cells (CSCs), also known as tumor-initiating cells, are a subpopulation of tumor cells that exhibit properties similar to those of normal stem cells. Oxygen is an important regulator of cellular metabolism; hypoxia-inducible factors (HIFs) mediate metabolic switches in cells in hypoxic environments. Hypoxia clearly has the potential to exert a significant effect on the maintenance and evolution of CSCs. Both HIF‑1α and HIF‑2α may contribute to the regulation of cellular adaptation to hypoxia and resistance to cancer therapies. This review provides an overview of the roles of HIFs in CSCs. HIF‑1α and HIF‑2α have significant prognostic and predictive value in the clinic and the concept of personalized medicine should be applied in designing clinical trials for HIF inhibitors.