* Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland† Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA‡ e-mail: jurg. tschopp@ ib. unil. ch ertain cytokines of the tumour-necrosis factor (TNF) family and their cognate receptors (collectively named death receptors) are potent inducers of programmed cell death (apoptosis) 1. One such protein is the cell-surface receptor Fas, which, upon ligand binding, trimerizes and recruits the adaptor protein FADD through the cytoplasmic death domain of Fas. FADD then binds and activates procaspase-8 (ref. 1). TRAIL, the most recently identified member of the TNF family of death ligands, can induce apoptosis in a wide variety of tumour cells but not in normal cells2. TRAIL induces apoptosis through two death-domain-containing receptors, TRAIL-R1 (also called death receptor (DR) 4) 3 and TRAIL-R2 (or DR5) 4–9. Investigation of the intracellular signalling pathways responsible for TRAIL-receptor-induced apoptosis has produced controversial results. Genetic evidence10, 11 indicates the