Glioblastoma is the most aggressive and most common grade 4 tumor of the central nervous system (CNS). Despite standard treatments such as surgical resection and chemoradiotherapy, overall survival (OS) usually does not exceed 14–16 months in clinical trials, and no improvement in OS has been demonstrated even with the use of vascular endothelial growth factor A (VEGFA) inhibitors such as bevacizumab. In response to radiotherapy, hypoxia-inducible factor (HIF) stabilization leads to activation of alternative pro-angiogenic pathways, increasing VEGF expression and tumor angiogenesis. Several clinical trials evaluating HIF-2α inhibitors as monotherapy in the absence of concurrent VEGF inhibition, have similarly failed to demonstrate a significant improvement in OS outcomes. This review provides a perspective on the combined use of VEGF and HIF inhibitors, and provides an insight into future studies.