Acute promyelocytic leukemia (APL) is characterized by reciprocal chromosomal translocations that always Involve the retinoic acid receptor-alpha (RARalpha) gene on chromosome 17. RARalpha variably fuses to the PML, PLZF, NPM, NuMA, and STAT 5b genes (X genes), leading to the generation of X-RARalpha and RARalpha-X fusion genes. The aberrant X-RARalpha proteins retain the dimerization domains of their parental proteins and therefore can act as dominant negative oncogenic products on both RARalpha/RXR and X pathways. Studies in transgenic mice harboring X-RARalpha and RARalpha-X fusion genes and In mice lacking X genes have helped unravel the molecular mechanisms underlying APL leukemogenesis, which lead to the development of novel therapeutic strategies. Moreover, transgenic mouse models of APL were useful to test in vivo the efficacy of these novel therapeutic approaches as well as of drug combinations such as retinoic acid and As2O3 that were previously known to be effective as single agents in human APL.