In higher eukaryotic organisms epigenetic modifications are crucial for proper chromatin folding and thereby proper regulation of gene expression. Epigenetics include DNA methylation, histone modifications, and microRNAs. First described in tumors, the involvement of aberrant epigenetic modifications has been reported also in other diseases, i.e. metabolic, psychiatric, inflammatory, and autoimmune. Deregulation of epigenetic mechanisms occurred in patients with rheumatoid arthritis, systemic lupus erythematosus, and scleroderma. Many questions remain: e.g. what is the cause of these epigenetic changes and how can we interfere in the pathological process? Here we discuss whether supplementation with methyl donors could represent a novel therapeutic concept for such diseases.