Despite the wide applications of enzymes in pharmaceutical industry, the development of many drug compounds does not benefit from the power of biological synthesis, as their therapeutic value relies on chemical motifs rarely present or even completely absent in biology. To extend the scope of biosynthesis to include these non-natural moieties, we will employ a mechanism-driven strategy to engineer natural metalloenzymes for abiological reactions important for drug development. An interdisciplinary platform that integrates protein engineering, organic synthesis, bioinformatics, and computational modeling will also be established to evolve metalloproteins for new-to-nature catalytic functions. Our research would expand the reaction scope of enzymatic catalysis tremendously and unlock ample opportunities for synthesis of bioactive molecules with unprecedented diversity. These research efforts will eventually lead to important applications in disease diagnosis, treatment, and prevention.