The acute human leukemias are associated with the presence of chimeric gene products that arise from spontaneous chromosomal translocations. The t(8;21) translocation gene product led to the discovery of the Eight Twenty-One (ETO) gene. When fused to RUNX1, ETO is thought to mediate the formation of a repressive complex at RUNX1-dependent genes. ETO has also been found to act as a co-repressor of the promyelocytic zinc finger and Bcl-6 oncoproteins, suggesting that it may play a common role as a transcriptional co-repressor leading to human disease. An analysis of ETO-mediated repression revealed that one of the key binding partners of ETO is the nuclear receptor co-repressor (N-CoR). It is shown that two highly conserved domains of ETO interact with repression domains I and III of N-CoR. One of the ETO domains displays significant homology to Drosophila TAF(II)110, whereas the other is a predicted zinc binding motif that engages a conserved PPLXP motif in repression domain III of N-CoR. Together, these domains of ETO cooperate in repression with N-CoR and the binding sites in N-CoR overlap with those for other repressive factors. Thus, ETO has the potential to participate in a number of repressive complexes, which can be distinguished by their binding partners and target genes.