The tumor necrosis factor (TNF) receptor superfamily is composed of several type I integral membrane glycoproteins that exhibit homology in their cystine- rich extracellular domains. Members of this family include TNF-RI and -RII, FAS, OX40, CD27, CD30 and CD40. Ligands for these receptors can be small, secreted proteins such as TNF, or type II integral membrane proteins, such as the CD40 ligand, CD40L. While the signal transduction mechanism of the TNF receptor superfamily is poorly understood, stimulation of cells with either TNF or soluble CD40L has been shown to induce the nuclear translocation of NFkB. Members of the TRAF family associate with activated TNF-R and CD40 and have been implicated in this process. The discovery of a novel protein, designated TANK, has shed light on the means by which TRAF activation of NFkB occurs. TANK is not only capable of binding to all three TRAFs, but also of synergizing with TRAF2 to activate the NFkB signaling cascade. TANK contains a regulatory carboxy terminal domain that maintains its inactivity in unstimulated cells. Upon its association with TRAF2, the inhibitory effect of this domain is overcome.