The naturally occurring tumour necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis through two death receptors, death receptor 4 (DR4) and death receptor 5 (DR5), that are expressed on the cell membrane. Binding of the ligand to the death receptors leads to activation of the extrinsic apoptosis pathway. Chemotherapy on the other hand stimulates the intrinsic apoptosis pathway via activation of p53 in response to cellular damage. Many cancer cells have mutations in p53 causing resistance to chemotherapy-induced apoptosis. Concomitant signalling through the extrinsic pathway may overcome this resistance. Moreover, enthusiasm for TRAIL as an anticancer agent is based on the demonstration of rhTRAIL-induced selective cell death in tumour cells and not in normal cells. In this review, we provide an overview of the TRAIL pathway, the physiological role of TRAIL and the factors regulating TRAIL sensitivity. We also discuss the clinical development of novel agents, i.e. rhTRAIL and agonistic antibodies, that activate the death receptors.