Retinoic acid (RA) cures more than 75% of patients with acute promyelocytic leukemia (APL). Here, we review the various anti-cancer activities of retinoids and rexinoids, alone and in combination with other drugs, with emphasis on the RA-dependent induction of a cancer-cell-selective apoptosis signaling pathway to which multiple anti-cancer signals converge. These findings identify the TRAIL (tumor-necrosis-factor-related apoptosis-inducing ligand) pathway as a central cell-autonomous anti-cancer weapon that can act independently of the immune system.