Vertebrate animals have developed sophisticated host defense mechanisms against potentially hostile antigens. These mechanisms mainly involve the immune system and the epithelial cells that cover the body surface. Accumulating studies have revealed that epigenetic mechanisms in collaboration with signal transduction networks regulate gene expression over the course of differentiation, proliferation and function of immune and epithelial cells. The epigenetic status of these cells is fine‐tuned under physiological conditions; however, its disturbance often results in the development of immunological disorders, namely inflammation. Certain environmental factors influence the differentiation and function of immune cells through epigenetic alterations. For example, commensal microbiota‐derived metabolites inhibit histone deacetylases to induce regulatory T cells, whereas some infectious agents induce DNA methylation, resulting in the development of cancer. These data imply that epigenetic regulation of host defense cells, which are usually the first to encounter external antigens, is implicated in disease development. Here, we highlight recent advances in our understanding of the molecular mechanisms by which the epigenetic status of immune and epithelial cells is controlled.