One of the best studied NF-κB signalling pathways is the TNF pathway. TNF stimulation results in the recruitment of TNF receptor-1-associated death domain (TRADD) protein and of receptor interacting protein 1 (RIP1), which function as adaptor proteins for the E3 ubiquitin ligases TNF receptor-associated factor (TRAF) 2 and TRAF5, which in turn bind the E3 ubiquitin ligases cellular inhibitor of apoptosis (cIAP) 1 and cIAP2 (Figure 1). On TNF stimulation, TNF-receptor bound RIP1 is rapidly modified by K63-linked polyubiquitin chains. TRAF2/5 and cIAP1/2 are good candidates for RIP1 ubiquitination, but the specific role of each is still unclear. The polyubiquitin chains on RIP1 are believed to create a scaffold to recruit the IKK and TAK1 complex via the ubiquitin-binding proteins NEMO and TAB1/2, respectively. The recent identification of a distinct E2/E3 enzyme complex that modifies NEMO with linear polyubiquitin chains and is essential for TNF-activated NF-κB signalling adds further complexity [22]. The exact role of protein-anchored polyubiquitin chains remains unclear, as it was recently suggested that unanchored polyubiquitin chains can directly activate the TAK1 complex [23].