Acetyl‐CoA is a key metabolite at the crossroads of metabolism, signaling, chromatin structure, and transcription. Concentration of acetyl‐CoA affects histone acetylation and links intermediary metabolism and transcriptional regulation. Transcriptional activation is typically associated with increased acetylation of promoter histones. However, this paradigm does not apply to transcriptional activation of all genes. Here we show that genes required for mitochondrial biogenesis are repressed by histone acetylation. During exponential growth of budding yeast cells in rich, glucose‐based medium, mitochondrial biogenesis is repressed and cells metabolize glucose predominantly by glycolysis. Under these conditions, the cellular level of acetyl‐CoA is high and global histone acetylation is also high. When glucose becomes limiting, the cells enter diauxic shift, upregulate mitochondrial activity and switch metabolism from glycolysis to oxidative phosphorylation. This metabolic transition is associated with a decreased cellular level of acetyl‐CoA. To probe the role of global histone acetylation in regulation of mitochondrial biogenesis and activity, we characterized yeast mutants that express nonacetylatable versions of histones H3 and H4. These mutants displayed increased mitochondrial biogenesis and activity. Taken together, our results suggest a model in which decreased global histone acetylation signals decreased glucose availability and results in a metabolic switch from fermentation to oxidative phosphorylation. This work is supported by a grant from the NIH (GM106324).