[en] Canonical activation of NF-kappaB is mediated via phosphorylation of the inhibitory IkappaB proteins by the IkappaB kinase complex (IKK). IKK is composed of a heterodimer of the catalytic IKKalpha and IKKbeta subunits and a presumed regulatory protein termed NEMO (NF-kappaB essential modulator) or IKKgamma. NEMO/IKKgamma is indispensable for activation of the IKKs in response to many signals, but its mechanism of action remains unclear. Here we identify TANK (TRAF family member-associated NF-kappaB activator) as a NEMO/IKKgamma-interacting protein via yeast two-hybrid analyses. This interaction is confirmed in mammalian cells, and the domains required are mapped. TANK was previously shown to assist NF-kappaB activation in a complex with TANK-binding kinase 1 (TBK1) or IKKepsilon, two kinases distantly related to IKKalpha/beta, but the underlying mechanisms remained unknown. Here we show that TBK1 and IKKepsilon synergize with TANK to promote interaction with the IKKs. The TANK binding domain within NEMO/IKKgamma is required for proper functioning of this IKK subunit. These results indicate that TANK can synergize with IKKepsilon or TBK1 to link them to IKK complexes, where the two kinases may modulate aspects of NF-kappaB activation.