Maston et al. showed that in human embryonic stem cells (ESCs), only 6 of the 14 human TATA-binding protein (TBP)-associated factors (TAFs) that make up the TFIID general transcription factor are present. They found that most active promoters in ESCs are bound by TAFs 3 and 5 and that the rest are bound by a newly identified complex containing the six ESC TAFs and TBP. Knockdown of one of the ESC TAFs or ectopic expression of one of the non-ESC TAFs induces differentiation, suggesting that the unusual TAF composition is required for pluriplotency.