Specification in mammalian embryos begins in the 16-cell morula with the emergence of the trophectoderm (TE, from which the placenta develops) and the inner cell mass (ICM, from which the embryo develops). Now, on p. 3827, Yagi and colleagues report that the transcription factor TEAD4 specifies the TE lineage at the start of mammalian development. The researchers show that Tead4, like the highly homologous Tead2 gene, is first expressed in the mouse two-cell embryo. Tead4-/- embryos develop to the morula stage, they report, but do not express TE-specific genes nor establish a TE lineage, and die before blastocyst formation and implantation. Tead2-/- embryos, by contrast, develop into viable adults. Tead4-/- embryos do, however, express ICM-specific genes and can produce embryonic stem cells, derivatives of the ICM. Furthermore, if Tead4 is only disrupted after implantation, Tead4-/- embryos complete development. Thus, the researchers conclude, Tead4 is the earliest known TE lineage specifier, the expression of which, during zygotic gene activation, triggers the eventual differentiation of totipotent blastomeres into TE.