Epigenetic, modifications of DNA and histones, i.e. heritable alterations in gene expression that do not involve changes in DNA sequences, are known to be involved in disease. Two important epigenetic changes that contribute to disease are abnormal methylation patterns of DNA and modifications of histones in chromatin. Epimutations, such as the hypermethylation and epigenetic silencing of tumor suppressor genes, have revealed a new area for cancer treatment. Studies using DNA methyltransferase inhibitors such as procaine, hydralazine, and RG108 have had promising outcomes against cancer therapy. Melatonin, one of the most versatile molecules in nature, may hypothetically be involved in epigenetic regulation. In this review, the potential role of melatonin in inhibiting DNA methyltransferase and epigenetic regulation is discussed.