Mutational inactivation of the p53 tumor-suppressor gene, which regulates apoptosis mainly via the cell-intrinsic pathway, reduces the sensitivity of many cancers to conventional treatments. Targeting the cell-extrinsic pathway, which triggers p53-independent apoptosis, offers a unique therapeutic strategy to induce apoptosis in cancer cells. This article focuses on two proapoptotic receptor agonists, recombinant human Apo2-ligand/TNF-related apoptosis-inducing ligand (rhApo2L/TRAIL) and Apomab, which activate death receptor (DR) 4 and/or DR5, thus stimulating the cell-extrinsic pathway. These agents are under investigation for the treatment of solid tumor and hematologic malignancies. Preclinical data indicate that both molecules cause significant regression or growth inhibition of malignant tumors without significant toxicity. Initial data on rhApo2L/TRAIL and Apomab from phase 1 safety trials also confirm that these agents are suitable for further clinical investigation.