Acute myeloid leukemia (AML) with a complex aberrant karyotype is a distinct biological entity. It is characterized by: (1) a sharp increase in incidence above age 50; (2) a characteristic pattern of chromosomal gain and, especially, loss, that is, of 5q14q33, 7q32q35, and 17p13, translating into reduced expression of genes in these regions; (3) a unique gene expression pattern including up-regulation of genes involved in DNA repair; (4) a high incidence of TP53 deletions and/or mutations; and (5) an overall unfavorable prognosis. Further unraveling the biology of AML with a complex aberrant karyotype by gene expression profiling may provide deeper insights into the pathogenesis of as well as the reasons for chemoresistance in this AML subtype. These data may be the basis for developing targeted therapeutic strategies to increase the cure rate in patients with AML and a complex aberrant karyotype. © 2005 Wiley-Liss, Inc.