Histone methylations are highly regulated by site-specific histone methyltransferases and demethylases. In this issue of Genes & Development, Sengoku and Yokoyama (pp. 2266–2277) demonstrate that a novel Zn-binding domain and the Jumonji domain of UTX/KDM6A (Lys demethylase 6A) recognize histone H3 and together function as a substrate specificity determinant for H3K27 demethylation. This study demonstrates the mechanism of site-specific demethylation by UTX/KDM6A and implicates that histone demethylases use diverse methods to accomplish target specificity.