INTRODUCTION: Multiple Sclerosis (MS) is a chronic, inflammatory, neurodegenerative demyelinating disease of the central nervous system (CNS). Unfortunately, MS causes important disability in young adults and its prevalence is increasing. While the etiology of MS etiology is not completely understood, it seems to be a multifactorial entity that is influenced by both genetic and epigenetic modifications. Epigenetic mechanisms add or remove different chemical groups for the activation or inhibition of gene expression to block the production of proinflammatory proteins. It is truly important to identify the factors that can trigger epigenetic changes in MS to complement the therapeutic approach, prevent disability and improve patients quality of life. Here, we have conducted a review of external factors that influence in MS and their epigenetic mechanisms. For example, hypomethylation can promote changes in the myelin and subsequent autoimmune reactions. Therapeutic tools can be used, including the histone deacetylase inhibitor Trichostatin A, which ameliorates demyelinating diseases in rodents. However, drugs are not only the therapeutic option: recent studies have also evaluated the therapeutic potential of several bioactive dietary components in neurodegeneration and axonal dysfunction. Numerous food-derived molecules exert important metabolic actions. These molecules include plant polyphenols such as catechins and isoflavones, Ω-3 and Ω-6 polyunsaturated fatty acids, short-chain fatty acids, sulfur-containing compounds such as dally sulfide and other compounds. Antioxidant and anti-inflammatory components in the diet involve transcription factors as well. However, many external factors have shown to influence MS, although no specific epigenetic mechanisms are known. CONCLUSION: In this review, we gather both established and new evidences about the genetic, epigenetic and environmental factors influencing MS and the dietary components that could modulate MS relapse and progression.