There are two central reasons why these agents may have been ineffective in treating GBM patients:1) all four FDA-approved EGFR-TKIs that have been tested so far in GBM patients (erlotinib [8, 9], gefitinib [8, 10], lapatinib [11], and afatinib [12]) do not cross the blood-brain barrier effectively; and 2) the extreme molecular and functional heterogeneity of EGFR, as mentioned above, could not be taken into account at the time these clinical trials were performed because this information was not yet understood [13–15]. Here, EGFR is linked to glioblastoma.