Epigenetic modifications, including those on DNA andhistones, have been shown to regulate cellular metabolismby controlling expression of enzymes involved in thecorresponding metabolic pathways. In turn, metabolic fluxinfluences epigenetic regulation by affecting the biosyntheticbalance of enzyme cofactors or donors for certainchromatin modifications. Recently, non-enzymatic covalentmodifications (NECMs) by chemically reactive metaboliteshave been reported to manipulate chromatin architectureand gene transcription through multiple mechanisms. Here,we summarize recent advances in the identification andcharacterization of NECMs on nucleic acids, histones, andtranscription factors, providing an additional mechanistic linkbetween metabolism and epigenetics.