Post-translational modification of histone proteins, including lysine methylation, regulate gene expression through recruitment of reader proteins to the nucleosome. Dysregulation of these events is prevalent in a wide range of diseases, such that there is much interest in developing selective inhibitors and probes for this class of proteins. However, with over 200 methyllysine reader proteins in humans, achieving selectivity can be challenging. We have taken a mechanistic approach coupled with high throughput screening to identify unique selectivity patterns in these proteins, establishing new mechanisms of action and providing new opportunities for selective inhibition. These findings will be discussed.