AbstractcAMP response element binding protein (CREB)‐binding protein (CBP) and p300 are two structurally related transcriptional co‐activators that activate expression of many eukaryotic genes. Current dogma would suggest that these transcriptional co‐activators have similar mechanisms of transcription regulation. Studies of CBP or p300 homozygotic mouse mutants indicate that normal embryogenesis requires the existence of both factors. However, whether this is indicative of a dosage effect of these two proteins, or whether these proteins play different roles in mouse embryo development is not clear. Here we demonstrated that both factors are first found in the cytoplasm of oocytes within primordial follicles, and that they enter into the oocyte nucleus at different stages of oocyte growth, suggesting that they may play different roles in gene expression during oocyte growth and development. Consistent with this model, in the pre‐implantation mouse embryos, from the two‐cell stage to the blastocyst stage, the localizations of CBP and p300 are different, at times opposite, indicating that CBP and p300 also have different functions in early mouse embryogenesis. Mol. Reprod. Dev. © 2006 Wiley‐Liss, Inc.