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Alterations in cellular metabolism are a key feature of the transformed phenotype. Enhanced macromolecule synthesis is a prerequisite for rapid proliferation but may also contribute to induction of angiogenesis, metastasis formation, and tumor progression, thereby leading to a poorer clinical outcome. Metabolic adaptations enable cancer cells to survive in suboptimal growth conditions, such as the limited supply of nutrient and oxygen often found in the tumor microenvironment. Metabolic changes, including activation of glycolysis and inhibition of mitochondrial ATP production, are induced under hypoxia to promote survival in low oxygen. FOXO3a, a transcription factor that is inhibited by the phosphatidylinositol 3-kinase/Akt pathway and is upregulated in hypoxia, has emerged as an important negative regulator of MYC function. Recent studies have revealed that FOXO3a acts as a negative regulator of mitochondrial function through inhibition of MYC. Ablation of FOXO3a prevents the inhibition of mitochondrial function induced by hypoxia and results in enhanced oxidative stress. This review will focus on the antagonism between FOXO3a and MYC and discuss their role in cellular bioenergetics, reactive oxygen metabolism, and adaptation to hypoxia, raising questions about the role of FOXO proteins in cancer.