Enabled by advances in structural determination, kinetic studies, and multiscale molecular modeling, the mechanistic detail of SAM MTases has been unveiled. Combination of binding isotope effect experiment and large-scale quantum mechanical calculations shows the dependence of ground state donor-acceptor distance on the catalytic efficiency of catechol-Omethyltransferase. Investigations into C-H hydrogen bonding have elucidated the role of these non-bonding interactions in ensuring catalytic efficiency. Analysis of charge transfer and electrostatics on four Class I SAM MTases has illustrated the ability of these enzymes to customize their electrostatic potentials to the intrinsic reactivity of their target substrates. Although SAM MTases involve diverse substrate scope with a wide range of intrinsic methyl-accepting capability, the kinetic properties of MTase-catalyzed reactions are largely consistent. A survey of 15 unique MTases from IntEnzyDB shows an average activation barrier of 12.7 kcal/mol with a standard deviation of 1.9 kcal/mol (Supporting Information, Table ). Similarity of turnover number across diverse substrates is not unique to SAM MTases and is observed in many classes of enzymes. The combination of diverse substrates and functional roles with consistent kinetic output suggests that SAM MTases have evolved to address the specific characteristics of each catalyzed reaction. However, the molecular origins behind the substrate kinetic homogeneity remain largely unknown.