AbstractThe BET subfamily of bromodomain‐containing genes is characterized by the presence of two bromodomains and a unique ET domain at their carboxyl termini. Here, we show that the founding member of this subfamily, Brd2, is an essential gene by generating a mutant mouse line lacking Brd2 function. Homozygous Brd2 mutants are embryonic lethal, with most Brd2−/− embryos dying by embryonic day 11.5. Before death, the homozygous embryos were notably smaller and exhibited abnormalities in the neural tube where the gene is highly expressed. Brd2‐deficient embryonic fibroblast cells were observed to proliferate more slowly than controls. Experiments to explore whether placental insufficiency could be a cause of the embryonic lethality showed that injecting diploid mutant embryonic stem cells into tetraploid wild‐type blastocysts did not rescue the lethality; that is Brd2‐deficient embryos could not be rescued by wild‐type extraembryonic tissues. Furthermore, there were enhanced levels of cell death in Brd2‐deficient embryos. Developmental Dynamics 238:908–917, 2009. © 2009 Wiley‐Liss, Inc.