The bromodomain protein BRD4 binds to acetylated histones and. activates transcriptional elongation of many genes. BRD4 occupies the TSS, gene body and numerous enhancers, including super-enhancers. We investigated the role of BRD4 in the development and activity of innate immunity by testing conditional Brd4 knockout mice. Our work was promoted by a number of recent papers reporting that small molecule inhibitors for BRD4 inhibit BRD4-acetyl histone interaction, and suppress blood cancer growth and reduce inflammation. These drugs are, thus believed to offer new therapeutic avenues to complex diseases. We show that Vav-Cre mediated Brd4 deletion in early embryos blocks the generation and differentiation of hematopoietic stem cells (HSCs). As a result, all immune cells, i.e., lymphocytes and myeloid cells as well as red blood cells were markedly reduced in Brd4 KO embryos leading to death in utero at around day 17- day18. This and additional data with later Brd4 deletion indicate that BRD4 is required for proliferation of developing immune cells at various stages. Brd4 deletion in post-mitotic macrophages displayed a less dramatic phenotype: induction of inflammatory cytokines and chemokines by LPS was only partially affected in Brd4 KO macrophages. ChIP-Seq analyses showed that BRD4 clusters on super-enhancers located near the genes controlling the myeloid lineage and inflammatory responses. Together, BRD4 affects every step of immune cell development and exerts complex regulatory influences on inflammation.