Abstract: Targeting tumor metabolism for therapeutic strategies has emerged over the last decade due to a display of reprogrammed metabolism such as glycolysis, the citric acid cycle (TCA-cycle), and fatty acid. Key contributing factors of the resistance to therapy are the heterogeneity of these tumors, diffuse and infiltrative growth, the presence of the blood brain barrier, and likely the plasticity of these tumors to reactivate alternate survival pathways. A rational therapeutic approach with improved central nervous system (CNS) penetration and extend patient life expectancy can be exploited by using genetic and pharmacological inhibition of the oxidative metabolic reprogramming and conducting high throughput drug screening.