Diseases arising in the CNS include glioblastoma (GBM), the most prevalent primary brain tumor and one of the most deadly of all diseases. Conventional therapies are, in most cases, unable to completely eradicate tumor cells and rapid post-therapeutic tumor recurrence results in patients’ mortality. Tumor heterogeneity of GBM is well recognized by three clinically relevant subtypes (proneural [PN], mesenchymal [MES] and classic) based on the unbiased clustering of gene signature [1,2]. However, molecular signaling events in cancer stem cells (CSCs), which may be closely associated with individual GBM subtypes, remain poorly understood. Recent studies, including ours, identified and characterized two mutually exclusive CSC subtypes with distinct molecular signatures [3,4]. MES CSCs, in particular, displayed more aggressive and radio-resistant phenotypes than PN CSCs, both in vitro and in vivo. Analysis of genome-wide expression profiles distinguished MES from PN CSCs and revealed a striking correlation to the corresponding MES or PN GBMs. In particular, the Notch pathway and PDGF receptor pathway are preferentially activated in PN CSCs, whereas NF-κB pathway and glycolysis-mediated metabolism pathway were preferentially activated in MES CSCs. Moreover, experimental inhibition of each of these pathways selectively attenuated the growth of the one, but not the other CSC subtype.