Activation of cell surface death receptors of the tumor necrosis factor (TNF) receptor superfamily by the appropriate ligands represents an attractive therapeutic strategy to induce cell death by apoptosis in cancer cells. However, the toxic effects of TNF-alpha and CD95/Fas ligand (FasL) in normal tissues have significantly hampered the clinical application of these ligands in cancer treatment. TNF-related apoptosis-inducing ligand (TRAIL/APO-2L), another member of the TNF family, has been shown to induce apoptosis selectively in many tumor cell lines. Interestingly, TRAIL treatment also results in significant growth suppression of TRAIL-sensitive human cancer xenografts in mice and nonhuman primates. At the same time, recombinant TRAIL and agonistic TRAIL receptor antibodies show no significant cytotoxicity in these studies. Despite some adverse effects of certain TRAIL preparations, activation of proapoptotic TRAIL receptors represents a promising approach in cancer therapy. Herein we review what is known about proapoptotic TRAIL signaling, the role of intracellular survival pathways in the regulation of resistance to TRAIL and the activation of non-apoptotic signaling by TRAIL. We also discuss the role of the TRAIL system in tumorigenesis and the results of clinical trials with recombinant TRAIL and various TRAIL receptor agonistic antibodies, either as monotherapy or in combination with targeted or conventional chemotherapy.