Master Regulator Pu.1 organizes the enhancer landscape required for stimulus-induced transcription in innate immune system cells. The lineage-determining TF Pu.1 pervasively binds to regulatory elements in the genome of macrophages and dendritic cells. Pu.1 binding is sufficient to promote the deposition of H3K4me1 in a nucleosome-free region. Pu.1 binding is essential for the access of a second group of TFs called ‘primers’, such as Junb, Irf4 and Atf3 for dendritic cells, able to prime for activation regions that are associated with stimulus-dependent gene induction. Environmental stimuli (e.g. response to LPS) trigger the recruitment of stimulus-dependent TFs, such as NF-κB, AP-1, IRFs and STATs family members, to a specific set of proinflammatory genes.