Prominent among cell surface molecules capable of initiating apoptosis are members of the tumour necrosis factor (TNF) family of ligands and receptors. Death-inducing members of the TNF receptor family each contain a cytoplasmic 'death domain' (DD): a protein-protein interaction motif critical for engaging downstream components of the signal transduction machinery. Following activation of these receptors by their cognate ligands, a death-inducing signalling complex (DISC) is formed by recruitment of cytoplasmic DD-containing proteins to the receptor DD. The best-studied death-inducing ligand-receptor pairs are TNF/TNF receptor-1 (TNFR1) and CD95L/CD95 (Fas, Apo-1). A more recently identified member of the TNF ligand family is TNF-related apoptosis-inducing ligand (TRAIL), Apo-2L, which induces apoptosis in a number of tumour cell lines, yet is relatively non-toxic to normal cells. Consistent with its lack of toxicity, TRAIL is constitutively expressed in many human tissues. This raises the conundrum of why tumour cells are sensitive to TRAIL-mediated apoptosis and normal tissues resistant. One possibility lies in the existence of a family of four membrane-bound TRAIL receptors (TRAIL-R1-R4), which although able to bind TRAIL, differ in their ability to transduce the death signal. Recently, this hypothesis has been challenged based on poor correlations between TRAIL receptor expression and TRAIL sensitivity. This suggests that other factors, such as TRAIL-induced NF-kappaB activation or death inhibitors including c-FLIP, are involved in determining differential sensitivity to TRAIL. We have investigated TRAIL sensitivity in primary tumour cells together with TRAIL-induced signalling pathways in both sensitive and resistant cell lines. Our results and their implications for the potential use of TRAIL in cancer therapy are discussed.