Notch signaling is involved in a variety of cell-fate decisions during development. Here we investigate the role of Notch signaling in apoptotic cell death of neural progenitors through the generation and analysis of cell type-specific conditional transgenic and knockout mice. We show that conditional expression of a constitutively active form of Notch1 in early neural progenitor cells, but not postmitotic neurons, selectively induces extensive apoptosis, resulting in a markedly reduced progenitor population. Conversely, attenuation of Notch signaling in Notch1 conditional knockout or Presenilin-1−/− mice results in reduced apoptosis of early neural progenitor cells. Furthermore, Notch activation in neural progenitor cells leads to elevated levels of nuclear p53 and transcriptional upregulation of the target genes Bax and Noxa, and the promotion of apoptotic cell death by Notch activation is completely suppressed by p53 deficiency. Together, these complementary gain-of-function and loss-of-function studies reveal a previously unappreciated role of Notch signaling in the regulation of apoptotic cell death during early mammalian neural development.