Inflammation mediated by the crosstalk between leukocytes and resident tissue cells is crucial for the maintenance of homeostasis. Because chemokine ligands and receptors, which recruit a variety of leukocytes, are widely distributed among tissues, it is important to understand the mechanisms regulating inflammatory disease. Chemokines such as CC-chemokine ligand 2 (CCL2) amplify and maintain inflammation through chemokine-cytokine networks after the recruitment of circulating leukocytes. Chemokine-dependent nonresolving inflammation occurs in the peripheral and central nervous systems, and underlies several intractable diseases, including cancer and neuropathic pain. The chronic upregulation of chemokines is often mediated by epigenetic mechanisms consisting of DNA methylation, histone modification, and nucleosome positioning. In particular, histone acetylation and methylation have been shown to play important roles in the upregulation of chemokine expression. In addition to CCL2, several other chemokines strongly contribute to neuropathic pain through epigenetic induction. Consequently, targeting epigenetic changes may have therapeutic potential for nonresolving inflammatory diseases such as neuropathic pain. Further research into the epigenetics of inflammatory diseases should promote the development of novel and effective treatment strategies for intractable inflammatory diseases.