Perturbed epigenetic landscape and deregulated microRNA networks are central to the permanent activation and aggressiveness of synovial fibroblasts in rheumatoid arthritis. Current anti-cytokine therapies, although effectively halting synovitis, cannot reverse the stably activated destructive phenotype of rheumatoid arthritis synovial fibroblasts,offering rather limited protection against ongoing joint destruction in rheumatoid arthritis. Targeting the deregulated epigenome of rheumatoid arthritis synovial fibroblasts is key to developing joint-protective strategies in rheumatoid arthritis. To date, different pathogenic mechanisms have been identified that can profoundly impact the epigenetic derangements in rheumatoid arthritis synovial fibroblasts, including increased consumption of S-adenosylmethionine,a principal methyl donor in DNA methylation reactions, together with deregulation of crucial DNA- and histonemodifying enzymes. Re-establishing globally disturbed DNA methylation patterns in rheumatoid arthritis synovial fibroblasts by supplementing S-adenosylmethionine while preventing its leakage into polyamine cycles may bea promising therapeutic strategy in rheumatoid arthritis and the first epigenetic treatment to target rheumatoid arthritis synovial fibroblasts at the scene of the crime. Given the dynamic nature and reversibility of epigenetic modifications, their involvement in human diseases and recent perspectives on epigenetic therapies in cancer, epigenetic targeting of rheumatoid arthritis synovial fibroblasts should be within future reach.