This research program focuses on addressing gaps in chemical structure and reactivity through the power of catalysis. Inspired by metalloenzymes, my laboratory designs, studies, and invents innovative tools for chemical synthesis that overcome the need for chiral auxiliaries and stoichiometric activating agents. The cross-coupling methods proposed feature the use of common functional groups (e.g., aldehydes, amines, alkynes, and alkenes) and generate new carbon-carbon and carbon-nitrogen bond with excellent atom economy. A wide range of chiral motifs can be accessed by this approach and the insights gained will ultimately enhance our ability to control chemical reactivity and build chemical structures. In turn, this knowledge greatly augments our ability to discover new medicines for treating human diseases, as well as prepare these medicines on large scale. The program features many new directions supported by compelling preliminary data including cyclase-inspired catalysis, shuttle catalysis, and tandem catalysis. Besides the practical value, this program will provide fundamental insights into the use of various catalysts, including rhodium, ruthenium, cobalt, and nickel, for the activation and functionalization of carbon-hydrogen bonds—a long standing challenge in modern organic chemistry.