In this issue of Blood, Tamburini and colleagues have studied the regulation of protein translation control in primary AML cells and describe a mTORC1-independent mechanism of regulation of the translation initiation complex that can be targeted with 4EGI-1, a small molecule inhibitor of translation, leading to death of the cells.(1) This and other recent studies add to a growing body of evidence that AML cells have a critical dependence on active protein translation, which may provide an Achilles' heel for the tumor cells that can be targeted therapeutically.