Both Notch and NFkappaB signaling pathways are well-known for regulating proliferation, differentiation and apoptosis. Recent studies have presented several lines of evidence supporting an integration of the Notch and NFkappaB signaling pathways in differentiation/maturation of a diverse range of cell types. It is notable that Notch and NFkappaB signaling pathways share many common features: (i) both are activated by common stimuli such as TNF-alpha and hypoxia, (ii) activated Notch (NICD) and NFkappaB mediate transcription by regulating corepressors such as SMRT/N-COR, and (iii) both regulate similar target genes such as Hes-1 and IkappaBalpha. This review expands on how the collaboration between these pathways may play an important role in the CNS. We will speculate on the mechanisms by which Notch and NFkappaB signaling may collaborate to regulate stem cell renewal and differentiation during brain development and function.