Small-cell lung cancer (SCLC) is a neuroendocrine tumor type with limited treatment options and poor prognosis. SCLC comprises multiple molecular subtypes that are defined by the expression of the lineage-related transcription factors ASCL1, NEUROD1, POU2F3, and more controversially, YAP1. SCLC exhibits remarkable plasticity with the capacity to transition between molecular states; because these states are associated with unique therapeutic susceptibilities, SCLC has been likened to a moving therapeutic target. While MYC's role in driving the ASCL1-to-NEUROD1 (A-to-N) transition is established, additional mechanisms governing SCLC plasticity remain largely obscure. A recent study by Duplaquet and colleagues, published in Nature Cell Biology, employs an innovative genetically engineered mouse model of SCLC harboring loss of KDM6A—a histone lysine demethylase mutated in approximately 2% of SCLC cases. KDM6A loss in SCLC alters chromatin accessibility and increases the potential for A-to-N plasticity in vivo. Through characterization of the epigenetic landscape, Duplaquet and colleagues identified histone methylation as a key regulator of SCLC plasticity. These findings provide not only a new model system for studying SCLC plasticity, but also identify new epigenetic mechanisms involved, which will ultimately be critical for designing more effective therapies.