We describe temporal and genetic analyses of partially rescued Rb mutant fetuses, mgRb:Rb−/−, that survive to birth and reveal specific defects in skeletal muscle differentiation. We show that in the absence of Rb, these fetuses exhibit increased apoptosis, bona fide endoreduplication, and incomplete differentiation throughout terminal myogenesis. These defects were further augmented in composite mutant fetuses, mgRb:Rb−/−:p21−/−, lacking both Rb and the cyclin-dependent kinase inhibitor p21^Waf1/Cip1. Although E2F1 and p53 mediate ectopic DNA synthesis and cell death in several tissues in Rb mutant embryos, both endoreduplication and apoptosis persisted in mgRb:Rb−/−:E2F1−/− and mgRb:Rb−/−:p53−/− compound mutant muscles. Thus, combined inactivation of Rb and p21^Waf1/Cip1 augments endoreduplication and apoptosis, whereas E2F1 and p53 are dispensable during aberrant myogenesis in Rb-deficient fetuses.