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Zhang, Qi, and colleagues demonstrated that overexpression of the histone methyltransferase EZH2 was sufficient to drive lung adenocarcinoma tumor igenesis in approximately 40% of mice. EZH2 overexpression altered chromatin structure to disrupt normal developmental pathways, and EZH2-addicted murine tumors had similar signaling profiles as a subset of EZH2-overexpressing human non–small cell lung cancers (NSCLC) that were EGFR- and KRAS-wild-type. EZH2 depletion suppressed the growth of EZH2-overexpressing lung adenocarcinoma cells in vitro and in vivo, prompting the development of an enzymatic EZH2 inhibitor, JQEZ5, which induced tumor regression and reduced H3K27me3 in mice bearing EZH2-driven tumors. Together, these findings suggest that EZH2 targeting may be effective in a subset of NSCLCs that overexpress EZH2. For details, please see the article by Zhang, Qi, and colleagues on page 1006.