The CD95 (Fas/APO‐1) and tumor necrosis factor (TNF) receptor pathways share many similarities, including a common reliance on proteins containing ‘death domains’ for elements of the membrane‐proximal signal relay. We have created mutant cell lines that are unable to activate NF‐kappaB in response to TNF. One of the mutant lines lacks RIP, a 74 kDa Ser/Thr kinase originally identified by its ability to associate with Fas/APO‐1 and induce cell death. Reconstitution of the line with RIP restores responsiveness to TNF. The RIP‐deficient cell line is susceptible to apoptosis initiated by anti‐CD95 antibodies. An analysis of cells reconstituted with mutant forms of RIP reveals similarities between the action of RIP and FADD/MORT‐1, a Fas‐associated death domain protein.