Multiple sclerosis (MS) is the most frequent autoimmune, inflammatory disease of the central nervous system. It is believed to be a multifactorial and multigenic disease. Despite numerous efforts to find a locus with hypothesis-free whole genome screens, no repeatable locus other than HLA could be found. Genomic screens use polymerase chain reaction (PCR) based methods to find a difference between patients and controls. This method is insensitive to differences other than disparities in the DNA sequence. The negative results of these efforts suggest that other mechanisms may be involved in MS pathophysiology. Epigenetics denotes all heritable mechanisms which result in a transcriptional difference without a change in the DNA sequence. In the last decade, there have been several findings implying the significance of epigenetic modifications as causal factors for multifactorial diseases like MS. Epigenetic factors might be affecting MS induction and clinical severity by modulating such diverse biological processes as X chromosome inactivation, viral infections, myelin protein production and Th1 type immune response differentiation.