Tumor cells with elevated levels of Notch activity can be divided into Notch signaling–dependent and –independent classes, which are based on their genetic or epigenetic background. For Notch-dependent tumor cells, GSI treatment can reduce Notch target gene expression and decrease propagation. However, shRPBJ in these same cells will release RBPJ-mediated repression of gene transcription, induce expression of Notch target genes, and increase tumor cell propagation. In contrast, in Notch-independent tumor cells, or GSI-resistant cells, GSI treatment still can block NICD formation and decrease Notch target gene expression. However, GSI treatment has no effect on propagation, because growth of Notch-independent tumor cells depends on genes that are not Notch targets. In this issue, Xie et al. demonstrate that knockdown of RBPJ in Notch-independent cells downregulates expression of genes, including FOXM1, CCNA2, and KRAS, that control brain tumor–initiating cell (BTIC) self-renewal and proliferation, and thereby decreases tumor growth through partnering with CDK9, which regulates elongation of RBPJ target genes. Furthermore, Xie et al. found that RBPJ is regulated by MYC and that blocking MYC expression, upstream of RBPJ, with JQ1 or blocking activity of CDK9 also decreases Notch-independent tumor cell propagation. Solid blue lines indicate results from Xie et al. Solid black lines indicate results from other reports.