Epigenetic drug discovery provides a wealth of opportunities for the discovery of new therapeutics but has been hampered by low hit rates, frequent identification of false-positives, and poor synthetic tractability. A key reason for this is that few screening collections consider the unique requirements of epigenetic targets despite significant medicinal chemistry interest. Here we analyze the suitability of some commercially available screening collections in the context of epigenetic drug discovery, with a particular focus on lysine post-translational modifications, and show that even privileged motifs found in U.S. Food and Drug Administration (FDA)-approved drugs are not present in these collections. We propose that the incorporation of epigenetic bioisosteres should become central in the design of new focused screening collections and highlight some opportunities for the development of synthetic methods which may improve the tractability of hit molecules.