Glioblastoma multiforme (GBM) lacks effective therapeutic options leaving patients with a survival time of approximately one year. Recently, the alteration of chromatin modulators has been implicated in the pathogenesis and chemoresistance of numerous cancers; in particular, the Polycomb Group Proteins have been shown to play a role in glioblastoma progression and maintenance [1-5]. In this study, we aimed to identify drug combinations that decrease GBM cell viability by combining small molecule inhibitors against the Polycomb family with two standard chemotherapies. We identified dual inhibition of the CBX chromodomain with doxorubicin as a novel therapeutic strategy. While treatment with chromodomain inhibitor is non-toxic to cells alone, it dramatically increased the toxicity of standard chemotherapy drugs. We further validated an increase in DNA damage resulting in a G2/M block and subsequent apoptosis using the dual inhibitor treatment.