Glioblastoma multiforme (GBM) is the most malignant and aggressive primary brain tumor in humans, with a uniformly poor prognosis. Hypoxia is a predominant feature in GBM and its microenvironment; it is associated with the tumor growth, progression and resistance to conventional therapy of cancers. Hypoxia-inducible factors (HIFs) are the master regulators of the transcriptional response to hypoxia in tumor cells and their microenvironment. Numerous studies indicated that hypoxia and HIFs played pivotal roles in the initiation, progression, therapy resistance and recurrence of GBM and maintained the phenotype of glioma stem cells (GSCs), which makes the prognosis of GBM patients worse. This review summarized the current research advance of hypoxia and HIFs in GBM progression and therapeutic implications, which will provide a better understanding of the contribution of hypoxia and HIFs to GBM initiation and progression and highlight that HIFs might be taken as the attractive molecular target approaches for GBM therapeutics.