Enhancer of Zeste homlog 2 (EZH2) is a catalytic subunit of epigenetic regulator Polycomb repressive complex 2 (PRC2), which trimethylates Lys 27 of histone H3, leading to silencing of the target genes that are involved in a variety of biological processes including tumor progression and stem cell maintenance. However, in addition to its canonical PRC2-dependent transcriptional repression function, EZH2 also acts as a gene activator in a noncanonical PRC2-independent manner. Overexpression of EZH2 has been detected in diverse cancers, and is associated with tumor malignancy. Moreover, activating mutations and inactivating mutations of EZH2 are also associated with certain types of cancer. Given EZH2’s multi-faceted function and role in cancer, context-specific strategy for targeting EZH2/EZH2-mediated signaling could serve as future targeted therapy/personalized medicine for human cancer.