Hypoxia induces expression of the RNA binding protein Lin28 by a mechanism that is sensitive to ERK signaling and class 1/2 HDAC activity. Lin28 destabilizes members of the miR-let-7 family, potent repressors of genes (Insrβ, Irs2, Igf1r) involved in glucose utilization, promoting an adaptive shift to glycolysis. However, let-7 also represses PIK3IP1, an inhibitor of Akt, thus cell survival signaling is impaired by let-7 loss. Restoration of let-7g during hypoxia boosts Akt signaling and improves cell survival.