Abstract The BCR–ABL fusion kinase is the driving mutation of chronic myelogenous leukemias and is also expressed in a subset of acute lymphoblastic leukemias. Recent advances in elucidating the structure, regulation, and signaling of BCR–ABL have led to the identification of allosteric sites that are distant from the ATP-binding pocket and are critical for BCR–ABL–dependent oncogenic transformation. Here, we review the available data regarding the molecular mechanism of action and the specificity of ATP-competitive tyrosine kinase inhibitors targeting BCR–ABL. In addition, we discuss how targeting of allosteric sites could provide new opportunities to inhibit resistant BCR–ABL mutants, either alone or in combination with conventional ATP-competitive inhibitors. Cancer Res; 72(19); 4890–5. ©2012 AACR.