The CuAAC click reaction was discovered as part of our extensive program on merging organic chemistry with solid phase peptide chemistry.1 Due to our development of the biocompatible PEG based polymers PEGA for peptides and SPOCC and POEPOP for more exotic organic reactions it was feasible to combine peptides with almost any of the known reactions including conditions of carbanion and carbenium ion chemistry. Subsequently we could screen on-bead for biological activity in aqueous buffers. The CuAAC between azide and bis-Cu(1) acetylide yielded exclusively the 1,4-triazole via the metallocycle-intermediate and the Cu(1) addition increased the rate of formation of the triazole with a factor 107.2 Most importantly the click reaction was completely orthogonal to other types of chemistry and allowed for ligation of large peptides with no protection. We used the click technology to stitch a variety of biologically active proteins together to combine functionality, but more importantly we used the click reaction to support structural features in proteins and peptides3 including such composed of completely unnatural amino acids. The structure of the triazole bridges were easily be tuned to suit a particular site in the protein and while mimicking the function of disulfide bonds they are not targets of the processing catabolic machinery of the cell. In order to design proteins with bio-function we focused on the four classes of proteases and developed a method coined Mutational Molecular Dynamics (MMD) for the de Novo design of synthetic proteolytic micro-enzymes and novel micro-protein recognition molecules. Several examples of the implementation of this powerful technology including use for receptor ligands, stabilization of antimicrobial peptides, protein conjugation, and artificial enzymes will be presented.