Hes genes are immediate targets of Notch and are implicated in maintaining the undifferentiated state in many stem cell-based systems throughout the animal kingdom. Earlier work from our lab showed that larval CNS hyperplasia induced by Notch depends on the integrity of the E(spl) locus (harbors 7 Hes genes), although in this context we could detect activation of many other genes by Notch. The CNS defects were due to excessive accumulation of neural stem cells, or neuroblasts (NBs), at the expense of differentiated neurons and glia. In the process of dissecting the genomic networks regulated by Notch in proliferating larval NBs, we sought to discern the part of the signal that is transduced via the Hes proteins. Indeed, we could produce similar CNS hyperplasias by overexpressing only Hes proteins; the most severe defects were obtained by coexpression of E(spl)mγ and deadpan (dpn), another Hes gene that responds to Notch in this tissue. We analyzed transcriptional profiles from hyperplastic CNSs overexpressing Hes proteins individually or in combination. Different Hes overexpressions had nearly identical transcriptomes, which also had 50% overlap with Nicd overexpressing CNSs, suggesting that a large part of the Notch signal is transduced via the Hes proteins. Although Hes proteins are repressors, there is good overlap in both down- and up-regulated genes of Nicd, suggesting an extensive degree of feedforward regulation. For example, the stemness promoting factor grh and the temporal transcription factors svp and cas were amongst the common upregulated genes. We went on to characterize in more detail top downregulated transcription factor genes. Of 6 TFs studied in depth, three are primarily expressed in differentiating neurons, two are expressed in late NBs and one is expressed in intermediate neural precursors of the Type II lineages. Loss of function of most of these genes resulted in no effect suggesting functional redundancy, however overexpression or misexpression of some of these factors led to premature NB loss. At least three of these downregulated targets contain regions that are bound by Dpn by ChIP, suggesting direct regulation. We propose that the Notch-Hes axis maintains NBs in an undifferentiated state by repressing a cohort of TF genes that promote terminal differentiation.