The field of cancer research has experienced significant momentum from the discovery that most malignant tumors harbor subpopulations of cancer cells with stem cell features. Consequently, identification and characterization of so-called cancer-initiating cells or cancer stem cells has also provided novel insights into the biology of malignant brain tumors. Despite an ongoing debate regarding the exact role and identity of cancer stem cells, several studies have suggested that this subpopulation is critical for tumor initiation, tumor progression, angiogenesis and resistance to available therapies. The study of signaling pathways critical to normal neural stem and progenitor cells has also increased our understanding of the mechanisms that drive cancer stem cell-associated tumorigenesis and tumor progression. Novel treatment strategies are being developed to selectively target the molecular pathways relevant to cancer stem cells. This review summarizes important signaling pathways employed by both normal and cancer stem cells and highlights promising molecular-targeted therapies interfering with those signaling pathways in malignant gliomas.