The way in which energy is used in cells is determined under the influence of environmental factors such as nutritional availability. Metabolic adaptation is mainly achieved through the modulation of metabolic gene expression, and may also involve epigenetic mechanisms that enable long-term regulation. Recent studies have identified that nutrients and their metabolites exert an important influence on the epigenome, as they serve as substrates and/or coenzymes for epigenetic-modifying enzymes. Some epigenetic factors have been shown to regulate metabolic genes leading to a shift in energy flow. These findings suggest the concept of metabolism-epigenome crosstalk that may contribute to the formation of a long-term metabolic phenotype. This is particularly relevant to the pathogenesis of obesity and associated metabolic disorders, in which pre- and post-natal nutritional conditions affect disease risks in adulthood. Moreover, most cancer cells exploit metabolic pathways for their hyperproliferative activity, while metabolic misregulation leads to aberrant epigenetic regulation in some cancers. This review explores the possible mechanisms of metabolism-epigenome crosstalk that may facilitate our understanding of physiology and diseases.