Retinoids modulate growth and differentiation of cancer cells through activation of gene transcription via the nuclear retinoic-acid receptors (RAR) and retinoid-X receptors (RXR). Their use in differentiation therapy of acute promyelocytic leukemia (APL) represents a model concept for reprogramming cancer cells. However, they also regulate antiproliferative genes whose functions do not mechanistically concur to this program. Recently, we have shown that, independently of maturation, a long-term all-trans retinoic acid (ATRA) treatment of the maturation-resistant APL cell line (NB4-LR1) represses telomerase (hTERT), leading to telomere shortening and death. Using retinoid-receptor-specific agonists, we demonstrate herein that cross-talk between RARalpha and RXR dual-liganded to their respective agonists resulted in strong synergistic downregulation of hTERT and subsequent cell death. Importantly, unlike ATRA, this synergy was obtained at very low agonist concentrations and occurred in other ATRA maturation-resistant APL cells. These findings provide the first demonstration that dual-liganded RXR and RARalpha signaling should allow efficient targeting of telomerase in differentiation-resistant tumor cells. Such a combination therapy might hold promise in clinic to avoid side effects of ATRA whose administration can indiscriminately activate all RARs. Given the tissue-specific expression of RARs, a tissue-selective therapy targeting telomerase in tumor cells by synthetic agonists can be envisioned.