Core binding factor (CBF) acute myeloid leukemia (AML) is cytogenetically defined by the presence of t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), which are found in approximately 15% of all adult de novo AML cases. At the molecular level, both cytogenetic abnormalities result in disruption of CBF, a transcription factor that functions as an essential regulator of normal hematopoiesis. Despite this molecular commonality, recent studies have demonstrated differences in genetic, clinical, and prognostic features between t(8;21) and inv(16)/t(16;16) AML, thereby supporting the notion that they represent two distinct biologic and clinical entities. Furthermore, despite being considered as a more favorable AML risk group, only approximately half of the CBF AML patients are cured with current therapy, indicating the need for improved therapeutic approaches. This review summarizes the most recent laboratory and clinical discoveries relevant to this subset of AML and how they are being applied for in an effort to improve the cure rate in patients with the disease.