The histone-modifying enzymes that catalyze reversible lysine acetylation and methylation are central to the epigenetic regulation of chromatin remodeling. From the early discovery of histone deacetylase inhibitors to the more recent identification of histone demethylase blockers, chemical approaches offer increasingly sophisticated tools for the investigation of the structure and function of these lysine-modifying enzymes. This review summarizes progress to date on compounds identified from screens or by design that can modulate the activity of classical histone deacetylases, sirtuins, histone acetyltransferases, histone methyltransferases and histone demethylases. We highlight applications of compounds to mechanistic and functional studies involving these enzymes and discuss future challenges regarding target specificity and general utility.