AbstractCatalytically active non‐metal cofactors in enzymes carry out a variety of different reactions. The efforts to develop derivatives of naturally occurring cofactors such as flavins or pyridoxal phosphate and the advances to design new, non‐natural cofactors are reviewed here. We report the status quo for enzymes harboring organocatalysts as derivatives of natural cofactors or as artificial ones and their application in the asymmetric synthesis of various compounds.