The striking efficiency of enzyme catalysis has inspired many organic chemists to explore enzyme mechanism(s) by studying certain intramolecular processes (enzyme models) which proceed faster than their intermolecular counterparts. This editorial describes the use of computational methods such as quantum mechanics and molecular mechanics to explore the mechanisms of various enzyme models for assigning the factors affecting the rate-limiting step and determining the mode and action of the reaction. Among the enzyme models discussed herein are: (a) proton transfer between two oxygen atoms and proton transfer between nitrogen and oxygen in Kirby’s enzyme model; (b) intramolecular acid-catalyzed hydrolysis in some of Kirby’s N-alkylmaleamic acids; (c) proton transfer between two oxygen atoms in Menger’s rigid system; (d) acid-catalyzed lactonization of hydroxy acids as studied by Cohen and (e) SN2-based cyclization as studied by Bruice. These enzyme models were utilized as linkers to be covalently attached to commonly used drugs having poor bioavailability or/and bitter sensation. The conversion rate of the prodrug to its active form is solely determined on the structural features of the linker