The inhibitor of kB kinase (IKK) complex, a critical positive regulator of nuclear factor kappaB (NF-kappaB) signaling and immune function, can be activated in vitro by polyubiquitin chains. The modification of signaling intermediates by polyubiquitin and their association with ubiquitin-binding domain-containing proteins within multimolecular signaling complexes therefore represent a potential mechanism for activation of IKK and NF-kappaB in vivo.