The bromodomain-containing proteins BRD2, BRD3, BRD4 and BRDT are epigenetic readers that are currently of substantial interest as therapeutic targets. These proteins recognize short protein sequences that contain acetyllysine residues. Small molecules targeting the acetyllysine-binding pocket are currently the subject of ~20 clinical trials, mostly focused in the area of cancer. These molecules, however, do not have particularly high affinities and are not selective for one of these proteins over the others. In an effort to find better bromodomain inhibitors, we have used the RaPID approach developed in Hiroaki Suga's laboratory to screen a library of approximately a trillion cyclic peptides containing unnatural amino acids. Our biophysical and structural data indicate that high-affinity, high-selectivity peptides that target the acetyllysine-binding pocket can be recovered using this strategy, opening the door to a completely new class of bromodomain inhibitors that could have substantial value as chemical biology tools and perhaps as therapeutic leads.