Cloning and characterization of the 8;21 chromosomal breakpoint identified AML1 on chromosome 21 and ETO (MTG8) on chromosome 8, and the resultant chimeric gene product, AML-1/ETO. The ETO gene family now includes three human members encoding proteins composed of four evolutionarily conserved domains termed nervy homology regions (NHR) 1-4. ETO associates with N-CoR/Sin3a/HDAC complexes in vivo and acts as a corepressor for the promyelocytic zinc finger protein. Moreover, ETO is nuclear matrix attached at sites coincident with histone deacetylase enzymes and mSin3a. These data suggest that ETO proteins function as transcriptional corepressors. This review focuses on the ETO gene family in terms of expression and function. Specifically, the role of ETO as a co-repressor will be detailed. Additionally, the impact of this recent discovery on treatment of t(8;21)-containing leukemia will be discussed.