Cancer stem cells (CSCs) show a remarkable sub class of cancer cells population which have a potential to organize and regulate stemness properties which possess a main particular responsibility for uncontrolled growth in carcinogenesis, production of different cancers in differentiated situation and also resistancy to radiotherapy and chemotherapy. Correspondingly, gastric cancer (GC) as a very serious type in cancer mortality in the world, has received a deep attention in molecular therapy recently. Besides the main characteristics of CSCs like differentiation, epithelial mesenchymal transition, self-renewal and metastasis, they are so effective in expression of stemness genes resistancy in radiotherapy and chemotherapy. In this way, the regulation of epigenetic elements including DNA methylation and the performance of DNA methyltransferase (DNMT) which is a notable epigenetic trait in GC, is of great importance. Inhibitors of DNA methylation are the first epigenetic drugs in cancer therapy. Considerably, recent studies indicate that low doses of DNMT inhibitors have a high potential in sustaining reduced DNA methylation and related with re-expression of silenced genes in tumorigenesis. Importantly, these certain doses have the ability to decrease the carcinogenesis and tumorigenesis in CSC populations within GC. Meaningly, the inhibition of DNMTs are able to reduce the accumulation of tumorigenic ability of GC CSCs. Furthermore, many epigenetic drugs have a great potential in cancer therapy, including histone methyltransferases, lysine demethylases, histone deacetylasesand, bromodomain and extra-terminal domain proteins and DNA methyltransferases inhibitors. In this review article, we try to focus on the therapeutic mechanism of DNMTs alongside with their impact on CSCs in GC.