Metabolic reprogramming is a central hallmark of cancer, enabling tumor cells to obtain the macromolecular precursors and energy needed for rapid tumor growth. Understanding how oncogenes coordinate altered signaling with metabolic reprogramming and global transcription may yield new insights into tumor pathogenesis, and provide a new landscape of promising drug targets, while yielding important clues into mechanisms of resistance to the signal transduction inhibitors currently in use. We review here the recently identified central regulatory role for mechanistic target of rapamycin complex 2 (mTORC2), a downstream effector of many cancer-causing mutations, in metabolic reprogramming and cancer drug resistance. We consider the impact of mTORC2-related metabolism on epigenetics and therapeutics, with a particular focus on the intractable malignant brain tumor, glioblastoma multiforme (GBM).