Tumor necrosis factor (TNF)-activated cell signaling is mediated primarily through the TNF receptor 1 (TNF-R1) and, to a lesser extent, TNF-R2. Both TNF receptors are members of the expanding TNF receptor superfamily, which includes the FAS antigen and CD40. Potential insight into an understanding of TNF receptor-mediated signaling was provided by the identification of two related proteins, TRAF1 and TRAF2 (for TNF receptor-associated factors 1 and 2, respectively). Both function to form heterodimeric complexes and associate with the cytoplasmic domain of TNF-R2. A third member of this protein family, alternatively designated CD40 bp, CRAF1, LAP1 or TRAF3, has been identified and shown to associate with the cytoplasmic domain of CD40. The similarity between a specific region of TRAF3 with regions of TRAF1 and TRAF2 define a “TRAF-C” domain that is necessary and sufficient for CD40 binding and homodimerization.