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Patients with somatic mutations of epigenetic regulators are characterized by aberrant chromatin modification patterns. Recent mechanistic studies pairing chemical tool compounds and deep-sequencing technology have greatly broadened our understanding of epigenetic regulation in glioma progression and underpinned alternative treatment of epigenetic inhibitors. However, the effect of most inhibitors is condition-dependent, and the overall results of clinical trials still have not been applied to patients. There is an intense need to develop more potent and specific compounds as well as identify the population who may achieve clinical benefits. Besides, combination therapy with conventional therapeutics is another alternative strategy. In this review, we summarize well-characterized chemical probes in glioma research and clinical translation. We also discuss the target population and combination of therapy regimens of various agents. In a holistic sense, we try to provide guidance for selecting targeted chemical probes and pave the way for personalized rational therapy.