Glioblastoma multiforme(GBM),designated as World Health Organization(WHO)grade IV astrocytoma,is a lethal and therapy-resistant brain cancer comprised of several tumor cell subpopulations,including GBM stem cells(GSCs)which are believed to contribute to tumor recurrence following initial response to therapies.Emerging evidence demonstrates that GBM tumors are initiated from GSCs.The development and use of novel therapies including small molecule inhibitors of specific proteins in signaling pathways that regulate sternness,proliferation and migration of GSCs,immunotherapy,and non-coding microRNAs may provide better means of treating GBM.Identification and characterization of GSC-specific signaling pathways would be necessary to identify specific therapeutic targets which may lead to the development of more efficient therapies selectively targeting GSCs.Several signaling pathways including mTOR,AKT,maternal embryonic leucine zipper kinase(MELK),NOTCH1 and Wnt/β-catenin as well as expression of cancer stem cell markers CD133,CD44,Oct4,Sox2,Nanog,and ALDHlA1 maintain GSC properties.Moreover,the data published in the Cancer Genome Atlas(TCGA)specifically demonstrated the activated PI3K/AKT/mTOR pathway in GBM tumorigenesis.Studying such pathways may help to understand GSC biology and lead to the development of potential therapeutic interventions to render them more sensitive to chemotherapy and radiation therapy.Furthemore,recent demonstration of dedifferentiation of GBM cell lines into CSC-like cells prove that any successful therapeutic agent or combination of drugs for GBM therapy must eliminate not only GSCs,but the differentiated GBM cells and the entire bulk of tumor cells. Glioblastoma multiforme (GBM), designated as World Health Organization (WHO) grade IV astrocytoma, is a lethal and therapy-resistant brain cancer comprised of several tumor cell subpopulations, including GBM stem cells (GSCs) which are believed to contribute to tumor recurrence following Preliminary response to therapies. Early evidence of that the GBM tumors are initiated from GSCs. The development and use of novel therapies including small molecule inhibitors of specific proteins in signaling pathways that regulate sternness, proliferation and migration of GSCs, immunotherapy, and non-coding microRNAs may provide better means of treating GBM.Identification and characterization of GSC-specific signaling pathways would be necessary to identify specific therapeutic pathways which may lead to the development of more efficient therapies targeted targeting GSCs.Several signaling pathways include mTOR, AKT, maternal embryonic leucine zipper kinase (MELK), NOTCH1 and Wnt / β-catenin as well as expres sion of cancer stem cell markers CD133, CD44, Oct4, Sox2, Nanog, and ALDH1A1 maintain GSC properties. More over the data published in the Cancer Genome Atlas (TCGA) specifically rendered the activated PI3K / AKT / mTOR pathway in GBM tumorigenesis. such pathways may help to understand GSC biology and lead to the development of potential therapeutic interventions to render them more sensitive to chemotherapy and radiation therapy. Furthemore, recent demonstration of dedifferentiation of GBM cell lines into CSC-like cells prove that any successful therapeutic agent or combination of drugs for GBM therapy must eliminate not only GSCs, but the differentiated GBM cells and the entire bulk of tumor cells.