Transcriptional activation of the interferon-β (IFN-β) gene requires assembly of an enhanceosome containing ATF-2/c-Jun, IRF-3/IRF-7, and NFκB. These factors bind cooperatively to the IFN-β enhancer and recruit coactivators and chromatin-remodeling proteins to the IFN-β promoter. We describe here a crystal structure of the DNA-binding domains of IRF-3, IRF-7, and NFκB, bound to one half of the enhancer, and use a previously described structure of the remaining half to assemble a complete picture of enhanceosome architecture in the vicinity of the DNA. Association of eight proteins with the enhancer creates a continuous surface for recognizing a composite DNA-binding element. Paucity of local protein-protein contacts suggests that cooperative occupancy of the enhancer comes from both binding-induced changes in DNA conformation and interactions with additional components such as CBP. Contacts with virtually every nucleotide pair account for the evolutionary invariance of the enhancer sequence.