TAF10 (formerly TAFII30), is a component of TFIID and the TATA box-binding protein (TBP)-free TAFcontaining complexes (TFTC/PCAF/STAGA). To investigate the physiological function of TAF10, we disrupted its gene in mice by using a Cre recombinase/LoxP strategy. Interestingly, no TAF10 / animals were born from intercrosses of TAF10 / mice, indicating that TAF10 is required for embryogenesis. TAF10 / embryos developed to the blastocyst stage, implanted, but died shortly after ca. 5.5 days postcoitus. Surprisingly, trophoblast cells from TAF10 / blastocysts were viable, whereas inner cell mass cells failed to survive, highlighting that TAF10 is not generally required for transcription in all cells. TAF10-deficient cells express normal levels of TBP and TAFs other than TAF10 but contain only partially formed TFIID, are endocycle arrested, and have undetectable levels of transcription. Thus, our results demonstrate that TAF10 is required for TFIID stability, cell cycle progression, and transcription in the early mouse embryo. Initiation of transcription at eukaryotic class II promoters is a multistep process requiring the coordinated action of many proteins. In general, RNA polymerase II (Pol II) and a host of other factors, including the general transcription factors TFIIA, -B, -D, -E, -F, and -H, work together to form a preinitiation complex (PIC) and allow subsequent transcription. The TATA-box-binding protein (TBP) and 14 evolutionarily conserved TBP-associated factors (TAFs) form TFIID (15). Multiple TFIID complexes exist, indeed nuclear extracts contain at least two subpopulations of TFIID: those that contain TAF10 and those that do not contain TAF10 (39). Electron microscopy has shown that TFIID contains surfaces that could mediate both extensive core promoter and protein-protein interactions (1, 4). Given its early requirement in vitro, as well as its capacity to direct PIC assembly on both TATA-containing and TATA-less promoters, TFIID was proposed to be a central component of the PIC. At present, the role played by TAFs in transcription is not fully understood. Nonetheless, in vitro transcription experiments have suggested that TAFs within TFIID function as coactivators by engaging in direct and selective interactions with transactivators and/or core promoter sequences (2). Furthermore, TAF1 (formerly TAFII250) (39) possesses kinase, histone acetyltransferase (HAT), and ubiquitin conjugating/ligating enzymatic activities (44), suggesting that TAFs can affect transcription at multiple levels. In yeast TAFs are required for viability, but strains lacking functional TAFs can activate transcription from a variety of inducible genes (38). Moreover, gene expression studies have demonstrated that TAFs have gene-selective effects, with histone fold domain (HFD)-containing TAFs having wide-ranging effects on transcription, whereas the effects of other TAFs appear to be more restricted (18, 23, 24). Taken together with experiments in Drosophila melanogaster and mammalian systems, these results suggest that TAFs, rather than being necessary for all activated transcription, have gene selective effects and therefore play specialized roles at certain subsets of promoters.