Traditionally, gene transcription has not been an area of strong focus for the development of therapeutics. However, in recent years there has been some success in drugging histone deacetylase and DNA methyltransferase enzymes, generating interest in treating disorders at the level of transcription. The family of BET bromodomain proteins have also recently created much excitement. These proteins contain bromodomains that interact with acetylated lysine residues on histones and also contain an extra terminal (ET) domain of unknown function. Clinical trials are already underway for drugs targeting the bromodomains of BET protein Brd4. With the success of drugging bromodomains, the scope has broadened to drugging other domains of BET proteins. Recent work has shown that the ET domain in BET protein Brd3 binds specifically to a KIKL- like motif that occurs in a number of transcriptional regulatory proteins. This interaction seems localized to a particular binding pocket in the ET domain, raising the question as to whether inhibition of ET-partner interactions might constitute a useful adjunct or alternative to inhibition of bromodomain activity. Recent work has been aimed at structural determination of the Brd3 ET domain complexed with a KIKL motif from a transcriptional regulator as well as a fragment based drug design screening.