Glioblastoma multiforme (GBM) is the most invasive type of gliomas. Glioblastoma stem cells (CSC) represent a rare fraction of human glioblastoma cells which result more radio and chemoresistant compared to relative tumor cells. Recently, we have reported that CSC from the core and peritumoral tissues (c and p-CSC) of the same GBM sample displayed different cell growth kinetics and tumorigenic potential. Since the great interest in developing targeted molecular therapies, we focused our attention on EGFR and NOTCH1 signaling. In this study, we treated CSC with ?-secretase inhibitor-X (GSI-X), a NOTCH1 signaling inhibitor either alone or along with an EGFR signaling inhibitor (AG1478), to examine their effects on c-CSC and p-CSC. Our results showed a low induction of late apoptosis/necrosis in c-CSC#2/3 with a negligible effect on cell cycle distribution by addition of GSI-X. A single AG1478 treatment significantly affects cell growth of all CSC with a concomitant increase of G1 phase fraction and induction of late apoptosis/necrosis of different entity observed in c-CSC#2/3 and at a lesser extent in p-CSC#2. The combination of AG1478 and GSI-X exacerbated apoptosis of aforementioned samples. In conclusion, concurrent EGFR and NICD1 inhibition triggers apoptosis in c-CSC pools predominantly, while the apoptotic escape of p-CSC pools might be explained by a compensatory PDGFR? activation. This approach could have a high relevance because able to target not only the tumor "sensu stricto" but also the peritumoral area, site of tumor recurrence in about 90% of cases.