Project Abstract Advances in molecule construction and diversification expedite drug discovery and development. Given the ubiquity of C–H bonds in molecules, methods to selectively convert them into functional groups represent one of the most attractive strategies to introduce diversity efficiently and enable rapid molecular construction. Despite significant advances, however, directly and selectively functionalizing complex molecules bearing multiple stereocenters and delicate functional groups remains a major challenge. Creative use of enzymes to perform new-to-nature C–H functionalization reactions can greatly accelerate such processes, while providing sustainable and more selective alternatives to currently used stoichiometric methods or noble metal catalysts. We propose to start from enzymes that derivatize complex bioactive molecules via C–H hydroxylation and engineer them by directed evolution to perform abiological C–H functionalization to furnish new C–C bonds or C–N bonds. We envision that these efforts will establish a versatile biocatalytic platform that will provide rapid access to derivatives of complex molecules with selectivity and efficiency unattainable by current synthetic approaches. This work will also illustrate evolutionary innovation mechanisms and the rapid acquisition of novel genetically encoded functions.