Technological breakthroughs are emphasizing the impact of epigenetic mechanisms in human health highlighting the importance of a fine-tune orchestration of DNA methylation, micro RNAs, histone modifications, and chromatin structure. Transcriptional regulators sense the concentration of intermediary metabolites associated to a wide variety of biological processes including the long-term imprinting and heritable DNA methylation. Recent epigenetic mechanisms associated with cholesterol and lipid homeostasis have a critical impact in the susceptibility, development and progression of complex diseases such as type 2 diabetes mellitus, non-alcoholic fatty liver, obesity and metabolic syndrome. The heritability of epigenetic states emerge as an additional level of complexity where the extension of somatic as well as inherited epigenetic modifications may require a thoughtful reconsideration in many human diseases related with metabolic disorders.