Apoptosis is integral to normal, physiologic processes that regulate cell number and results in the removal of unnecessary or damaged cells. Apoptosis is frequently dysregulated in human cancers, and recent advancements in our understanding of the regulation of programmed cell death pathways has led to the development of novel agents to reactivate apoptosis in malignant cells. The activation of cell surface death receptors by tumor necrosis factor–related apoptosis-inducing ligand (Apo2L/TRAIL) and death receptor agonists represent an attractive therapeutic strategy to promote apoptosis of tumor cells through the activation of the extrinsic pathway. The observation that Apo2L/TRAIL can eliminate tumor cells preferentially over normal cells has resulted in several potential therapeutics that exploit the extrinsic pathway, in particular, the soluble recombinant human (rh)Apo2L/TRAIL protein and agonist monoclonal antibodies that target death receptors 4 or 5. Many of these agents are currently being evaluated in phase 1 or 2 trials, either as a single agent or in combination with cytotoxic chemotherapy or other targeted agents. The opportunities and challenges associated with the development of death receptor agonists as cancer therapeutics, the status of ongoing clinical evaluations, and the progress toward identifying predictive biomarkers for patient selection and pharmacodynamic markers of response are reviewed. Clin Cancer Res; 16(6); 1701–8