Mammalian central nervous system (CNS) development is a highly organized process involving the precise and coordinated timing of cell-cycle exit, differentiation, survival, and migration. These events require proper expression of pro-neuronal genes but also repression of alternative cell fates and restriction of cell-type-specific gene expression. Here, we show that the cyclin-dependent kinase (CDK) inhibitor p57Kip2 interacted with pro-neuronal basic helix-loop-helix (bHLH) factors such as Mash1, NeuroD, and Nex/Math2. Increased levels of p57Kip2 inhibited Mash1 transcriptional activity independently of CDK interactions and acted as a direct repressor in transcriptional assays. Proliferating telencephalic neural progenitors co-expressed basal levels of Mash1 and p57Kip2, and endogenous p57Kip2 accumulated transiently in the nuclei of neural stem cells (NSCs) during early stages of astrocyte differentiation mediated by ciliary neurotrophic factor (CNTF), independent of cell-cycle exit and at times when Mash1 expression was still prominent. In accordance with these observations, gain- and loss-of-function studies showed that p57Kip2 repressed neuronal differentiation after mitogen withdrawal, but exerted little or no effect on CNTF-mediated astroglial differentiation of NSCs. Our data suggest a novel role for p57Kip2 as a context-dependent repressor of neurogenic transcription factors and telencephalic neuronal differentiation.