Increasing attention has been focused on the use of agonistic monoclonal antibodies against TNF-related apoptosis-inducing ligand (TRAIL) death receptors DR4 or DR5 as a potential cancer treatment. These antibodies have strong apoptosis-inducing activity against cancer cells and potent antitumor activity against tumor xenografts in preclinical models that are enhanced by combination chemotherapy treatment. There are several agonistic humanized or human monoclonal antibodies against DR4 and DR5 that have been tested in Phase I and II trials in patients with advanced cancer. These trials have demonstrated these antibodies to be well tolerated, and to produce prolonged stable disease, which is the best antitumor effect in patients with advanced cancer. Clinical studies in which TRAIL-receptor antibodies are being investigated in combination treatment regimens in patients with advanced cancer are ongoing. It is anticipated that the results from a broad spectrum of cancer therapy clinical trials will identify the activity and toxicity profiles of TRAIL death-receptor antibodies as a single agent, or in combination with chemotherapy agents or radiation therapy.