Background: To maintain homeostasis, cells need to coordinate the expression of their genes. Epigenetic mechanisms controlling transcription activation and repression include DNA methylation and post-translational modifications of histones, which can affect the architecture of chromatin and/or create 'docking platforms' for multiple binding proteins. These modifications can be dynamically set and removed by various enzymes that depend on the availability of key metabolites derived from different intracellular pathways. Therefore, small metabolites generated in anabolic and catabolic processes can integrate multiple external and internal stimuli and transfer information on the energetic state of a cell to the transcriptional machinery by regulating the activity of chromatin-modifying enzymes. Scope of review: This review provides an overview of the current literature and concepts on the connections and crosstalk between key cellular metabolites, enzymes responsible for their synthesis, recycling, and conversion and chromatin marks controlling gene expression. Major conclusions: Whereas current evidence indicates that many chromatin-modifying enzymes respond to alterations in the levels of their cofactors, cosubstrates, and inhibitors, the detailed molecular mechanisms and functional consequences of such processes are largely unresolved. A deeper investigation of mechanisms responsible for altering the total cellular concentration of particular metabolites, as well as their nuclear abundance and accessibility for chromatin-modifying enzymes, will be necessary to better understand the crosstalk between metabolism, chromatin marks, and gene expression.