Abstract: Discoveries made over the last decade have shown that critical changes in cancer cells, such as activation of oncogenes and silencing of tumor suppressor genes are caused not only by genetic but also by epigenetic mechanisms. While epigenetic alterations are somatically heritable, in contrast to genetic changes, they are potentially reversible, making them perfect targets for therapeutic intervention. Covalent modifications of chromatin, such as methylation of DNA and acetylation and methylation of histones, are important components of epigenetic machinery. Multiple recent studies have shown that epigenetic modifiers are candidates for potent new drugs in multiple cancers’ therapies, including gliomas, and several clinical trials are ongoing. However, as with other chemotherapeutic drugs, toxicity is one of the main concerns with some of the potent epigenetic drugs. Synergistic combinations of these agents are one approach to overcoming toxicity issues while enhancing efficacy. In this study we demonstrated that while individually BIX01294, an inhibitor of histone methyltransferase G9a, DZNep, an inhibitor of lysine methyltransferase EZH2, and Trichostatin A (TSA), an inhibitor of histone deacetylase at their low concentrations showed a moderate effect on the viability of U87 glioblastoma cells, in combinations they exhibited a synergistic effect. Importantly, these combinations exhibited minimal effect on adipose mesenchymal stem cells (AD-MSCs) growth. Thus, unique combinations and concentrations of epigenetic modifiers, that synergistically attenuated the U87 glioblastoma cells while exhibiting minor or moderate effects on normal stem cell growth, have been discovered.