All-trans-retinoic acid (ATRA) plays critical regulatory roles in normal haematopoiesis and the pathogenesis of adult and pediatric acute myeloid leukemia (AML). While ATRA can inhibit growth and stimulates myeloid differentiation via RARα, it is equally potent in causing expansion of haematopoietic stem cells via RARγ. RARG mRNA is expressed in AML patients and normal stem/progenitor cells but not in more mature myeloid cells. Changes in RARγ expression are paralleled by a reciprocal change in expression of RARG 3’-targeting miRNAs (mIR-24, mIR-30a, mIR-331). RARγ protein and RARG mRNA are also expressed in cell lines derived from primary AML samples but not in ATRA-responsive AML cell lines. Lastly, expression of mIR-30a in TEX cells promotes differentiation and inhibits proliferation. Our results suggest that miRNA-mediated down-regulation of RARγ expression in the myeloid lineage switches ATRA responsiveness from RARγ-mediated pro-proliferation to RARα-mediated pro-differentiation and that the combinatorial use of RARα and RARγ selective agonists and antagonists, respectively, could be effective in retinoid-based differentiation therapy of AML.