Unlike conventional cancer therapeutics, death receptor ligands trigger tumor cell apoptosis independently of the p53 tumor suppressor gene, which frequently is inactivated in cancer. The death receptor ligand Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) offers promising therapeutic potential based on its ability to induce apoptosis in various cancer cell lines with little toxicity toward normal cells. Moreover, Apo2L/TRAIL displays single-agent activity and cooperates with chemotherapy or radiotherapy in a variety of tumor xenograft mouse models. Thus, Apo2L/TRAIL might be effective against tumors that have acquired resistance to conventional therapy, and could augment the efficacy of current treatment in a wide spectrum of cancers.