Release of E2F1/DP1 heterodimers from repression mediated by the retinoblastoma tumor suppressor (pRB) triggers cell cycle entry into S phase,suggesting that E2F1 and DP1 proteins must act in unison, either to facilitate or to suppress cell-cycle progression. In stark contrast to the milder phenotypes that result from inactivation of E2Fs, we report that loss ofDp1 leads to death in utero because of the failure of extra-embryonic development. Loss of Dp1 compromises the trophectoderm-derived tissues — specifically, the expansion of the ectoplacental cone and chorion, and endoreduplication in trophoblast giant cells. Inactivation ofp53 is unable to rescue the Dp1-deficient embryonic lethality. Thus, DP1 is absolutely required for extra-embryonic development and consequently embryonic survival, consistent with E2F/DP1 normally acting to promote growth in vivo.