Stem cells undergo metabolic reprogramming and use different metabolic substrates during differentiation. Now, Vittorio Sartorelli and colleagues report that proliferating skeletal muscle stem cells (called satellite cells) shift from fatty acid oxidation to glycolysis, with downstream effects on epigenetic states and gene expression (Cell Stem Cell 16, 171–183, 2015). The authors analyzed the transcriptomes of quiescent and proliferating mouse satellite cells and observed transcriptional activation of the glycolytic program. They found that the shift to glycolysis was accompanied by a decrease in the levels of NAD+, a corresponding decrease in the activity of the NAD+-dependent enzyme SIRT1 and an increase in H4K16ac, the substrate of SIRT1-mediated deacetylation. The authors generated a skeletal muscle–specific knockout of Sirt1, which exhibited defects in skeletal muscle development and regeneration following injury. They used RNA-seq and ChIP-seq to profile gene expression and SIRT1 and H4K16ac localization across the genome to determine links between SIRT1, H4K16ac and gene expression. This work connects metabolic shifts with epigenetic regulation in tissue stem cells.