PML-RARA was proposed to initiate acute promyelocytic leukemia (APL) through PML-RARA homodimer-triggered repression. Here, we examined the nature of the PML-RARA protein complex and of its DNA targets in APL cells. Using a selection/amplification approach, we demonstrate that PML-RARA targets consist of two AGGTCA elements in an astonishing variety of orientations and spacings, pointing to highly relaxed structural constrains for DNA binding and identifying a major gain of function of this oncogene. PML-RARA-specific response elements were identified, which all conveyed a major transcriptional response to RA only in APL cells. In these cells, we demonstrate that PML-RARA oligomers are complexed to RXR. Directly probing PML-RARA function in APL cells, we found that the differentiation enhancer cyclic AMP (cAMP) boosted transcriptional activation by RA. cAMP also reversed the normal silencing (subordination) of the transactivating function of RXR when bound to RARA or PML-RARA, demonstrating that the alternate rexinoid/cAMP-triggered APL differentiation pathway also activates PML-RARA targets. Finally, cAMP restored both RA-triggered differentiation and PML-RARA transcriptional activation in mutant RA-resistant APL cells. Collectively, our findings directly demonstrate that APL cell differentiation parallels transcriptional activation through PML-RARA-RXR oligomers and that those are functionally targeted by cAMP, identifying this agent as another oncogene-targeted therapy.