Acute myeloid leukemia (AML) was initially subdivided according to morphology (the French-American-British system), which proved helpful in pathologic categorization. Subsequently, clinical and genomic factors were found to correlate with response to chemotherapy and with overall survival. These included a history of antecedent hematologic disease, a history of chemotherapy or radiation therapy, the presence of various recurrent cytogenetic abnormalities, and, more recently, the presence of specific point mutations. This article reviews the biology and responses of one AML subgroup with consistent response and good outcomes following chemotherapy (core-binding factor leukemia), and two subgroups with persistently bad, and even ugly, outcomes (secondary AML and TP53-mutated AML).