The mammalian gastrointestinal tract is home to trillions of commensal microorganisms that collectively make up the intestinal microbiota. These microbes are important environmental factors that regulate homeostasis, and alterations in the composition of the microbiota have been associated with several diseases, including inflammatory bowel disease, diabetes, and cancer. New research is beginning to uncover epigenomic pathways that may regulate this relationship with the microbiota. Epigenomic modifications alter the structure of the chromatin and therefore regulate the transcriptional program of a cell. These modifications are maintained by the dynamic activity of various modifying and demodifying enzymes, the activities of which can be influenced by metabolites and other environmental cues. Histone deacetylases (HDACs) are a class of epigenomic-modifying enzymes that are regulated by both endogenous and exogenous factors, and recent studies have suggested that host HDAC expression is important for regulating communication between the intestinal microbiota and mammalian host cells.