Glioblastoma multiforme (GBM, WHO grade IV) is the most aggressive and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. Recent studies indicate that some neoplastic cells within human high-grade glioma have the capacity for self-renewal and multi-lineage differentiation, properties associated with normal neural stem cells. These stem-like tumor cells known as GBM stem cells (GSCs) are responsible for tumor progression and recurrence. Therefore, GSCs are attractive targets for novel glioma therapies. Mounting studied have evidenced that some molecular signaling pathways (including EGFR, PI3K, PDGFR, TGF and Notch.), which are critically important for GSCs self-renew and proliferation, are activated by genetically mutation or amplification in GSCs. Targeting these molecules might be promising novel treatment strategies to eliminate GSCs, however, crosstalk and compensation between different signaling pathways as well as intratumoral heterogeneity make it more complicate and a big challenge.