Glioblastoma multiform (GBM) is the most common malignant glioma of all the brain tumors and currently effective treatment options are still lacking. GBM is frequently accompanied with overexpression and/or mutation of epidermal growth factor receptor (EGFR), which subsequently leads to activation of many downstream signal pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt/rapamycin-sensitive mTOR-complex (mTOR) pathway. Here we explored the reason why inhibition of the pathway may serve as a compelling therapeutic target for the disease, and provided an update data of EFGR and PI3K/Akt/mTOR inhibitors in clinical trials.