Apo2 ligand or tumour necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is one of the several members of the tumour necrosis factor (TNF) gene superfamily that induce apoptosis through engagement of death receptors (DRs). Apo2L/TRAIL interacts with an unusually complex receptor system of two DRs and three decoys. This protein has garnered intense interest as a potential candidate for cancer therapy because as a trimer it selectively induces apoptosis in many transformed cells but not in normal cells. While much of the early characterisation of Apo2L/TRAIL and its receptors relied on overexpression studies, recent work using untransfected cells has clarified how endogenous proteins transmit apoptotic signals from this ligand. In this review, we focus on the apoptotic signalling pathways stimulated by Apo2L/TRAIL and summarise what is known about its physiological role.