The NF-kappa B p50/p65 heterodimer is the classical member of the Rel family of transcription factors which regulate diverse cellular functions such as immune response, cell growth, and development(1-3). Other mammalian Rel family members, including the proteins p52, proto-oncoprotein c-Rel, and RelB, all have amino-terminal Rel-homology regions (RHRs)(4-7). The RHR is responsible for the dimerization, DNA binding and cytosolic localization of these proteins by virtue of complex formation with inhibitor kappa B proteins(8), Signal-induced removal of kappa B inhibitors allows translocation of dimers to the cell nucleus and transcriptional regulation of kappa B DNA-containing genes(9), NF-kappa B specifically recognizes kappa B DNA elements(1,10,11) with a consensus sequence of 5＇-GGGRNYYYCC-3＇ (R is an unspecified purine; Y is an unspecified pyrimidine; and N is any nucleotide), Here we report the crystal structure at 2.9 Angstrom resolution of the p50/p65 heterodimer bound to the kappa B DNA of the intronic enhancer of the immunoglobulin light-chain gene, Our structure reveals a 5-base-pair 5＇ subsite for p50, and a 4-base-pair 3＇ subsite for p65, This structure indicates why the p50/p65 heterodimer interface is stronger than that of either homodimer, A comparison of this structure with those of other Rel dimers reveals that both subunits adopt variable conformations in a DNA-sequence-dependent manner. Our results explain the different behaviour of the p50/p65 heterodimer with heterologous promoters.