Epigenetic enzymes are emerging as crucial controllers of macrophages, innate immune cells that determine the outcome of many inflammatory diseases. Recent studies demonstrate that the activity of particular chromatin-modifying enzymes is regulated by the availability of specific metabolites like acetyl-coenzyme A, S-adenosylmethionine, α-ketoglutarate, nicotinamide adenine dinucleotide and polyamines. In this way chromatin-modifying enzymes could sense the macrophage's metabolic status and translate this into gene expression and phenotypic changes. Importantly, distinct macrophage activation subsets display particular metabolic pathways. IFNγ/lipopolysaccharide-activated macrophages (MIFNγ/LPS or M1) display high glycolysis, which directly drives their inflammatory phenotype. In contrast, oxidative mitochondrial metabolism and enhanced polyamine production are hallmarks and requirements for IL-4-induced macrophage activation (MIL-4 or M2). Here we report how epigenetics could serve as a bridge between altered macrophage metabolism, macrophage activation and disease.