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As tumors evolve, they undergo metabolic state transitions in response to flux of nutrients, O2, and therapy. The evolving cancer-genome undergoes several intended and unintended mutations, amplifications, insertions and deletions. These dynamic changes create metabolic vulnerability and impose great burden on cancer cells. To thrive, evolving cancer cells acquire a remarkably altered metabolic and signaling flexibility. Identifying genes that protect tumor cells against cell-intrinsic vulnerabilities and the hostile tumor environment may provide novel therapy in human cancer. The multifunctional kinase AMPK is an evolutionarily conserved energy/stress sensor that plays important yet undefined role during tumor evolution. AMPK activated by the tumor suppressor LKB1 or the calcium-regulated kinase CAMKK2. AMPK inhibits mTOR and lipogenesis and therefore not surprisingly, many laboratories found that agents (e.g., metformin, now in several clinical trials) that activate AMPK suppress tumor growth. However, a few recent studies questioned this over-simplistic model. Using glioblastoma multiforme (GBM) as a model, we found that the AMPK pathway is constitutively active in human GBM and in a clinically relevant genetically engineered mouse model of high grade glioma. The AMPK-HIF1 alpha axis was earlier shown to play a tumor suppressive role in a mouse model of lymphoma. Unexpectedly, we uncovered that the AMPK-HIF1 alpha axis plays a tumor promoting role in GBM. Biochemical, genetic and metabolic experiments showed that AMPK positively regulates a HIF1alpha and GABPA-dependent transcriptional program of GBM bioenergetics that allows optimal energy metabolism and survival. Unfortunately, there are no specific AMPK inhibitors. Therefore, using multiple genetic tools to reduce, or express (rescue) targets of the AMPK- HIF1alpha-GABPA pathway in vivo and in vitro, we observed that AMPK is essential for GBM growth and survival.