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Core binding factor acute myelogenous leukemia (CBF AML) constitutes 15% of adult AML and carries an overall good prognosis. CBF AML encodes two recurrent cytogentic abnormalities referred to as t(8;21) and inv (16). The two CBF AML entities are usually grouped together but there is a considerable clinical, pathologic and molecular heterogeneity within this group of diseases. Recent and ongoing studies are addressing the molecular heterogeneity, minimal residual disease and targeted therapies to improve the outcome of CBF AML. In this article, we present a comprehensive review about CBF AML with emphasis on molecular heterogeneity and new therapeutic options. Am. J. Hematol. 89:1121–1131, 2014. © 2014 Wiley Periodicals, Inc.