Chromatin regulatory proteins are increasingly recognized as potential new drug targets. Many of these proteins harbor one or more so called 'reader domains' that recognize covalent modifications of lysine and arginine residues, typically on histones, which mediate specific interactions within chromatin. Here we review recent progress in the discovery of drug-like small molecules that antagonize the function of methyl-lysine and methyl-arginine reader domains (Royal family, plant homeodomain (PHD) and WD40 domains) as well as the acyl-lysine-binding YEATS domain.