AbstractMany cases of acute myelogenous leukemia (AML) are characterized by non‐random chromosomal translocations that fuse a DNA‐binding protein with a transcriptional regulator, which in turn may aberrantly recruit a co‐repressor complex. The similarities in this pattern between different AML chimeric fusions have led to a paradigm that stresses the importance of the co‐repressor complex in altering the pattern of expression of genes targeted by the DNA‐binding moiety of the fusion. Such findings beg the question of whether the fusion proteins merely serve as anchors to recruit the co‐repressor complex or whether they play other significant roles in leukemogenesis. The answers to this question may have therapeutic importance since we now have the ability to target various components of the co‐repressor complex, such as the histone deacetylase (HDAC) enzymes. In this Prospect, we wish to highlight some of the complexities and difficulties with the existing molecular paradigm of this challenging group of disorders. J. Cell. Biochem. 94: 864–869, 2005. © 2005 Wiley‐Liss, Inc.