Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) plays a critical role in the pathogenesis of cancer including glioblastoma, the most common and aggressive form of brain cancer. Targeting the PI3K pathway to treat glioblastoma has been tested in the clinic with modest effect. In light of the recent finding that PI3K catalytic subunits (PIK3CA/p110α, PIK3CB/p110β, PIK3CD/p110δ, and PIK3CG/p110γ) are not functionally redundant, it is imperative to determine whether these subunits play divergent roles in glioblastoma and whether selectively targeting PI3K catalytic subunits represents a novel and effective strategy to tackle PI3K signaling. This article summarizes recent advances in understanding the role of PI3K catalytic subunits in glioblastoma and discusses the possibility of selective blockade of one PI3K catalytic subunit as a treatment option for glioblastoma.