Oncogenic signaling pathways and tumor suppressors mediate metabolic reprograming in cancer to increase tumor growth and proliferation. Signaling cascades, such as Ras, PI3K and mTORC1, regulate metabolism and overexpression or mutations in components of these pathways contribute to altered metabolism in cancer. Additionally, signaling cascades stabilize transcription factors, such as HIF1 and c-Myc, which control metabolic gene expression to increase glycolysis or glutaminolysis. Mitochondrial sirtuins, SIRT3 and SIRT4, repress aberrant metabolism in cancer. SIRT3 represses reactive oxygen species (ROS) by deacetylating direct targets, such as manganese superoxide dismutase (SOD2) and isocitrate dehydrogenase (IDH2), to destabilize HIF1 and repress the Warburg effect. SIRT4 ADP-ribosylates glutamate dehydrogenase (GDH), and thus, represses glutaminolysis. (see colour version of this figure at www.informahealthcare.com/bmg).