Small peptides are an ideal class of therapeutics to target protein-protein interactions (PPIs) considering their low toxicity and ability to mimic the large interacting domain of a protein. Nevertheless, they remain underexplored compared to traditional small drug-like compounds due to intrinsic limitations: relative low stability in the living organism, as well as difficulty to adopt a highly ordered bioactive conformation. To overcome those limitations, two different approaches are well established for engineering PPIs peptidic inhibitors: 1) grafting residues, called “hotspots”, strongly interacting with a targeted protein onto a stable 3D structured scaffold; 2) introducing a covalent conformational constraint through macrocyclization, for instance by cross-linking two side-chains, so-called “stapling”, onto the peptidic hotspot-containing backbone. In our group, we are developing biocompatible protocols enable to generate libraries of potent peptidic PPI inhibitors based on Protein-Directed Dynamic Combinatorial Chemistry (P-D DCC). This method allows the creation of peptidic libraries under thermodynamic control which, upon addition of the biological target, can be re-equilibrated and lead to the amplification of the best inhibitor; thus bypassing expensive and time-consuming parallel synthesis and screening of large library of peptides. Recently, we described a new strategy based on thioester exchange reactions, to dynamically graft amino acids side-chains onto a structurally ordered peptidic beta-hairpin scaffold, and we are currently working on dynamic stapling of unstructured peptide for targeting alpha-helix involved PPIs.