The deregulation of homeobox (HOX) genes in acute myeloid leukemia (AML) and the potential for these master regulators to perturb normal hematopoiesis is well established. To date, overexpression of HOX genes in AML has been attributed to specific chromosomal aberrations and abnormalities involving mixed-lineage leukemia (MLL), an upstream regulator of HOX genes. The finding reported in this issue of the JCI by Scholl et al. that caudal-type homeobox transcription factor 2 (CDX2), which is capable of affecting HOX gene expression during embryogenesis, is overexpressed in 90% of patients with AML and induces a transplantable AML in murine models provides an alternative mechanism for HOX-induced leukemogenesis and yields important insights into the hierarchy of HOX gene regulation in AML (see the related article beginning on page 1037).