Nur77 is an orphan receptor and a member of the nerve growth factor-I-B subfamily of the nuclear receptor family of transcription factors. Based on the results of transactivation assays in pancreatic and other cancer cell lines, we have now identified for the first time Nur77 agonists typified by 1,1-bis(3-indolyl)-1-(p-anisyl)methane that activate GAL4-Nur77 chimeras expressing wild-type and the ligand binding domain (E/F) of Nur77. In Panc-28 pancreatic cancer cells, Nur77 agonists activate the nuclear receptor, and downstream responses include decreased cell survival and induction of cell death pathways, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and poly(ADP-ribose) polymerase (PARP) cleavage. Moreover, the transactivation and apoptotic responses are also induced in other pancreatic, prostate, and breast cancer cells that express Nur77. In Panc-28 cells, small inhibitory RNA for Nur77 reverses ligand-dependent transactivation and induction of TRAIL and PARP cleavage. Nur77 agonists also inhibit tumor growth in vivo in athymic mice bearing Panc-28 cell xenografts. These results identify compounds that activate Nur77 through the ligand binding domain and show that ligand-dependent activation of Nur77 through nuclear pathways in cancer cells induces cell death and these compounds are a novel class of anticancer agents.