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▸ RA synovial fibroblasts display an aberrant DNA methylome signature. ▸ Histone deacetylase inhibitors have beneficial effects in RA. ▸ Histone deacetylase inhibitors have epigenetic and non-epigenetic effects.Rheumatoid arthritis is an autoimmune disease characterized by chronic joint inflammation and progressive destruction of cartilage and bone which leads to ultimately loss of function and pain. Activated synovial fibroblasts are key effector cells in the pathogenesis of rheumatoid arthritis. In the recent years, epigenetic changes including DNA methylation, histone acetylation and other histone modifications were identified that are associated with an intrinsic activation and the aggressive phenotype of these cells. So far, no therapies targeting rheumatoid arthritis synovial fibroblasts exist. This review comprises recent research efforts that propose epigenetic mechanisms behind the activation of rheumatoid arthritis synovial fibroblasts and other cell types.