The first identified biochemical hallmark of tumor cells was a shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis. We now know that much of this metabolic conversion is controlled by specific transcriptional programs. Recent studies suggest that activation of the hypoxia-inducible factor (HIF) is a common consequence of a wide variety of mutations underlying human cancer. HIF stimulates expression of glycolytic enzymes and decreases reliance on mitochondrial oxidative phosphorylation in tumor cells, which occurs even under aerobic conditions. In addition, recent efforts have also connected the master metabolic regulator AMP-activated protein kinase (AMPK) to several human tumor suppressors. Several promising therapeutic strategies based on modulation of AMPK, HIF and other metabolic targets have been proposed to exploit the addiction of tumor cells to increased glucose uptake and glycolysis.