Despite continued advances in surgical and medical therapies, the outcomes for patients diagnosed with glioblastoma multiforme remain dismal. Recent data suggest that progression of these brain tumors is driven by a small subpopulation of tumor cells, which are termed cancer stem cells (CSCs) because of their capability to self-renew, proliferate and give rise to progeny of multiple neuroepithelial lineages. According to the CSC hypothesis, current therapies that are extremely cytotoxic to the bulk of highly proliferative tumor cells fail to obliterate the relatively quiescent and resistant CSC compartment, thereby allowing these cells to survive and drive tumor recurrence. This Review summarizes current knowledge regarding neural stem cells in the normal adult brain and CSCs in glial tumors and discusses the implications of the CSC hypothesis for the development of future therapies for brain tumors.