Genomic predisposition cannot explain the onset of complex diseases, as well illustrated by the largely incomplete concordance among monozygotic twins. Epigenetic mechanisms, including DNA methylation, chromatin remodelling and non-coding RNA, are considered to be the link between environmental stimuli and disease onset on a permissive genetic background in autoimmune and chronic inflammatory diseases. The paradigmatic cases of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren's syndrome (SjS) and type-1 diabetes (T1D) share the loss of immunological tolerance to self-antigen influenced by several factors, with a largely incomplete role of individual genomic susceptibility. The most widely investigated epigenetic mechanism is DNA methylation which is associated with gene silencing and is due to the binding of methyl-CpG binding domain (MBD)-containing proteins, such as MECP2, to 5-methylcytosine (5mC). Indeed, a causal relationship occurs between DNA methylation and transcription factors occupancy and recruitment at specific genomic locus. In most cases, the results obtained in different studies are controversial in terms of DNA methylation comparison while fascinating evidence comes from the comparison of the epigenome in clinically discordant monozygotic twins. In this manuscript, we will review the mechanisms of epigenetics and DNA methylation changes in specific immune-mediated rheumatic diseases to highlight remaining unmet needs and to identify possible shared mechanisms beyond different tissue involvements with common therapeutic opportunities. Key Points • DNA methylation has a crucial role in regulating and tuning the immune system. • Evidences suggest that dysregulation of DNA methylation is pivotal in the context of immune-mediated rheumatic diseases. • DNA methylation dysregulation in FOXP3 and interferons-related genes is shared within several autoimmune diseases. • DNA methylation is an attractive marker for diagnosis and therapy.