Human preimplantation development is a highly dynamic process that lasts about 6 days. During this time, the embryo must complete a complex program that includes activation of embryonic genome transcription and initiation of the pluripotency program. Here, Juan Carlos Izpisua Belmonte and co-workers use pico-profiling (an accurate transcriptome amplification method) to reveal the timing of sequential waves of transcriptional activation in single human oocytes and embryos (see p. 3699). The researchers (who have developed HumER, a free, searchable database of their gene expression data) report that initiation of transcriptional activity in human embryos starts at the 2-cell stage rather than at the 4- to 8-cell stage as previously reported. They also identify distinct patterns of activation of pluripotency-associated genes and show that many of these genes are expressed around the time of embryonic genome activation. These results link human embryonic genome activation with the initiation of the pluripotency program and pave the way for the identification of factors to improve epigenetic somatic cell reprogramming.