The Toll and Imd pathways induce humoral innate immune responses in Drosophila by activating NF-kappaB proteins that bind kappaB target sites. Here, we delineate a kappaB site sequence code that directs pathway-specific expression of innate immune loci. Using bioinformatic analysis of expression and sequence data, we identify shared properties of Imd- and Toll-specific response elements. Employing synthetic kappaB sites in luciferase reporter and in vitro binding assays, we demonstrate that the length of the (G)(n) element in the 5' half-site and of the central (A,T)-rich region combine to specify responsiveness to one or both pathways. We also show that multiple sites function to enhance the response to either or both pathways. Together, these studies elucidate the mechanism by which kappaB motifs direct binding by particular Drosophila NF-kappaB family members and thereby induce specialized innate immune repertoires.