Extensive apoptosis occurs in the nervous system of mouse embryos homozygous mutant for a targeted disruption of the retinoblastoma (Rb) gene. This cell death is present in both the central (CNS) and peripheral nervous systems (PNS) and is associated with abnormal S phase entry of normally post-mitotic neurons. Aberrant proliferation in the CNS correlates with increased free E2F DNA binding activity and increased expression of cyclin E, an E2F target gene and critical cell cycle regulator. Cell death in the CNS is accompanied by increased levels of the p53 tumor suppressor gene product and increased expression of the p53 target gene, p21Waf-1/Cip-1. However, induction of p53 is not observed in the PNS of Rb-mutant embryos, nor does loss of p53 function inhibit cell death in the PNS. Surprisingly, p21Waf-1/Cip-1 is induced in the sensory ganglia of Rb-mutant embryos in a p53-independent manner. Although loss of p53 gene function prevents cell death in the CNS of Rb-mutant embryos, it does not restore normal proliferative control.