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The present review introduces recent outstanding progress pertaining to Enhancer of zeste homolog 2 (EZH2), especially regarding its mode of action as a master regulator of chromatin, and provides molecular-based evidence for targeting EZH2 in cancer therapy. We discuss the active development of small molecules targeting the enzymatic activity of EZH2/polycomb repressive complex 2 (PRC2).Genetic, transcriptional, and posttranscriptional dysregulation of EZH2 is frequently observed in many cancer types. EZH2 promotes tumorigenesis by altering the expression of numerous tumor suppressor genes. Furthermore, the executive molecular processes initiated by EZH2, such as NF-κB activation, microRNA silencing, tumor immune evasion, and noncanonical transcription regulation, appear to be the fundamental characteristics of each cancer. Systematic investigations have suggested coordinated regulation of the cancer epigenome wherein antagonistic complexes of both polycomb and SWI/SNF are involved. Frequent loss-of-function mutations in epigenetic factors, such as ARID1A, SMARCA4, SMARCB1, BAP1, and KDM6A, are likely to elicit the EZH2/PRC2-addicted situation. Our comprehensive understanding encourages the development of advanced strategies for the appropriate manipulation of the cancer epigenome. Moreover, a couple of small molecules that can effectively inhibit the enzymatic activity of EZH2/PRC2 have been translated into early-phase clinical trials.The EZH2-mediated epigenome and subsequent transcriptome define cellular identity. Effective and specific strategies for the manipulation of EZH2/PRC2 may lead to the development of more precise cancer medicines.