The process of IgE switching requires the prior transcription of the unrearranged Cε gene, which leads to its recombination with the VDJ region. The activation of NF-κB by CD40 is a key process in facilitating this transcription by promoting the activation of the Cε promoter. The present study explores the uncharacterized signalling pathways employed by CD40 in activating NF-κB by the overexpression of genes encoding wild-type and dominant-negative forms of the signalling components tumour-necrosis-factor-receptor-associated factor 6 (TRAF-6), NF-κB-inducing kinase (NIK), IκB kinase (IKK)-1 and IKK-2 in the BJAB B-cell line. The overexpression of TRAF-6 or NIK was sufficient to activate NF-κB and the Cε promoter, whereas their dominant-negative counterparts decreased the ability of CD40 to activate NF-κB and the Cε promoter. The overexpression of wild-type IKK-1 or IKK-2 seemed to cause toxic effects on the cells, whereas the dominant-negative forms were selective in their blockade of NF-κB and the Cε promoter. These results suggest that CD40 employs TRAF-6, which presumably recruits NIK, which in turn employs IKK-1/IKK-2 to activate NF-κB and the Cε promoter, the prologue to IgE switching. Thus the findings define a crucially important pathway in the generation of allergic states.