The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a central regulator of cell proliferation, migration, tumor growth, survival, angiogenesis and metabolism, contributing to the malignant phenotype of gliomas. Trials using targeted therapeutics against growth factor receptors and downstream signal mediators of the PI3K pathway have demonstrated only modest clinical benefit. Although recent clinical data suggests that malignant gliomas with PTEN are more likely to respond to EGF receptor inhibitors, gliomas have multiple concomitantly activated pathways, making them highly resistant to single-targeted therapy. This review discusses the importance of the PI3K pathway in glioma, the potential role of PTEN status in directing specific therapies, discusses clinical trial development of drug combinations to treat malignant gliomas and offers strategies for trial design that will be necessary to fully understand the successes and failures of current approaches to glioma therapy.