Acute myeloid leukemia (AML) with t(8;21) or inv(16) is commonly referred to as core-binding factor AML (CBF-AML). The incorporation of high-dose cytarabine for postremission therapy has substantially improved the outcome of CBF-AML patients, especially when administered in the setting of repetitive cycles. For many years, high-dose cytarabine was the standard treatment in CBF-AML resulting in favorable long-term outcome in approximately half of the patients. Therefore, CBF-AML patients are generally considered to be a favorable AML group. However, a substantial proportion of patients cannot be cured by the current treatment. Additional genetic alterations discovered in CBF-AML help in our understanding of the process of leukemogenesis and some of them may refine the risk assessment in CBF-AML and, importantly, also serve as targets for novel therapeutic approaches. We discuss the clinical and genetic heterogeneity of CBF-AML, with a particular focus on the role of KIT mutations as a prognosticator, and also discuss recent efforts to target the KIT kinase in the context of existing therapeutic regimens.