Malignant gliomas remain refractory to conventional treatment approaches, including radiotherapy and cytotoxic chemotherapy. Molecular neuro-oncology has now begun to clarify the transformed phenotype of high-grade gliomas and identify oncogenic pathways that might be amenable to small molecule “targeted” therapy. Growth factor signaling pathways are often up-regulated in these tumors and contribute to oncogenesis through autocrine and paracrine mechanisms. Excessive growth factor receptor stimulation can also lead to overactivity of the downstream Ras signaling pathway. Other internal signal transduction pathways that may become dysregulated during transformation include PI3K, Akt, and mTOR. In addition, function of the cell cycle and apoptotic pathways are often abnormal in malignant glial cells. “Targeted” therapy against the growth factor signaling and Ras pathways include tyrosine kinase inhibitors (e.g., imatinib, erlotinib) and farnesyltransferase inhibitors (e.g., R115777). Molecular therapeutic small molecules specific to PI3K and mTOR include LY294002 and CCI-779, respectively. “Targeted” approaches to the apoptosis and cell cycle pathways include small molecular modulators, peptide CDK inhibitors, and proteasomal inhibitors. Further development of “targeted” therapies designed to modulate the activity of these pathways, and evaluation of these new agents in clinical trials, will be needed to improve survival and quality of life for patients with malignant gliomas.