Macrocyclic peptides emerge as compelling scaffolds for the design and development of diverse and potent therapeutic agents. These peptides exhibit extraordinary selectivity and high affinity for their targets and their potential to be adapted as therapeutics is reflected by the widespread abundance of macrocyclic peptides in nature as robust bioactive compounds. Random nonstandard Peptide Integrated Discovery (RaPID) is a ribosomal synthesis-based technique that has been developed to enable the discovery of effective ligands for any protein of interest from enormous libraries of non-standard amino acid incorporated cyclic peptides. We have used the RaPID approach to isolate cyclic peptide inhibitors of the acetyllysine-binding bromodomains of the Bromodomain and Extraterminal domain (BET) family of epigenetic regulators. The peptides enriched by RaPID boast superior selectivity and affinity to their previously developed small-molecular BET bromodomain inhibitor counterparts. The structures of several cyclic peptide-bromodomain complexes demonstrate a high degree of conformational preorganisation of the peptides and we find significant structural diversity among the different peptides isolated from the screens. Our findings together provide insight into the mechanistic basis behind these high affinity interactions and highlight the efficacy of RaPID in producing powerful ligands.