Abstract Summary: Recently, small-molecule inhibitors of general transcriptional regulators such as BET proteins and the RNA-PolII–regulating kinase CDK7 have been shown to have efficacy in multiple solid and liquid tumors. An article in this issue of Cancer Discovery identifies a nongenetic mechanism of resistance related to deficiency of folate that leads, via increased S-adenosylhomocysteine and reduced repressive histone methylation, to reactivation of a transcriptional program which promotes AML cell survival under the pressure of BET inhibition. See related article by Su et al., p. 1894.