Whereas nature uses post-translational modifications (PTMs) to manipulate protein structure and function, natural proteins are exclusively composed of 22 genetically-encoded (proteinogenic) amino acids. In principle, the design of proteins bearing unique residues can expand the structural and chemical space and might allow the development of new reactivities that do not exist in nature. Indeed, research has shown that the rational insertion of non-proteinogenic amino acids into polypeptides can lead to a dramatic refinement of key structural and functional features, such as folding, stability, and activity. Although these unique reactivities have been explored in peptides, the precise and high-resolution incorporation of non-natural residues or transformations into proteins remains limited and warrants further investigation. This challenge arises from the complexity of generating well-defined, sitespecifically modified abiotic proteins using conventional biological methods.