The future strategies to promote the potential of PI3K inhibitors for GBM treatment need to focus upon: [1] identifying genetic alternations such as PI3KCA mutations, PTEN mutations/loss and RAS mutations prior to the treatment regime; [2] rational combinations with other molecules’ inhibitors or other therapies, on the basis of understanding of the crosstalks between PI3K and other signaling molecules/pathways; [3] employing a BBB-permeable drug delivering system specifically targeting GBM cells to decrease toxicities on normal cells. The gene discussed is PIK3CA; the disease is glioblastoma.