Cyclic peptide libraries have successfully been employed for the identification of inhibitors of highly challenging targets. While several methodologies exist for the generation of cyclic peptide libraries, genetically encoded libraries hold several advantages over purely in vitro methods of library generation, including the ability to conduct cell-based functional screens and straightforward hit deconvolution. Here we detail the use of split-intein circular ligation of peptides and proteins (SICLOPPS) for the identification and optimization of several first-in-class and best-in-class inhibitors. We describe the current advances in the identification of SICLOPPS-derived inhibitors, as well as the optimization of library generation through the use of new inteins. Finally, we discuss the production of more diverse libraries as a way of enhancing the hit rate against difficult protein-protein interactions.