Eukaryotic complexity and thus their ability to respond to diverse cues are largely driven by varyingexpression of gene products, qualitatively and quantitatively. Protein adducts in the form of post-translationalmodifications, most of which are derived from metabolic intermediates, allow fine tuning of gene expressionat multiple levels. With the advent of high-throughput and high-resolution mapping technologies there hasbeen an explosion in terms of the kind of modifications on chromatin and other factors that govern geneexpression. Moreover, even the classical notion of acetylation and methylation dependent regulation oftranscription is now known to be intrinsically coupled to biochemical pathways, which were otherwiseregarded as ‘mundane’. Here we have not only reviewed some of the recent literature but also havehighlighted the dependence of gene regulatory mechanisms on metabolic inputs, both direct and indirect. Wehave also tried to bring forth some of the open questions, and how our understanding of gene expression haschanged dramatically over the last few years, which has largely become metabolism centric. Finally,metabolic regulation of epigenome and gene expression has gained much traction due to the increasedincidence of lifestyle and age-related diseases.