Density-functional and semiempirical quantum methods and continuum dielectric and explicit solvation models are applied to study the role of solvation on the stabilization of native and thio-substituted transphosphorylation reactions. Extensive comparison is made between results obtained from the different methods. For the semiempirical methods, explicit solvation was treated using a hybrid quantum mechanical/molecular mechanical (QM/MM) approach and the implicit solvation was treated using a recently developed smooth solvation model implemented into a d-orbital semiempirical framework (MNDO/d-SCOSMO) within CHARMM. The different quantum and solvation methods were applied to the transesterification of a 3‘-ribose,5‘-methyl phosphodiester that serves as a nonenzymatic model for the self-cleavage reaction catalyzed by the hammerhead and hairpin ribozymes. Thio effects were studied for a double sulfur substitution at the nonbridging phosphoryl oxygen positions. The reaction profiles of both the native and double sulfur-substituted reactions from the MNDO/d-SCOSMO calculations were similar to the QM/MM results and consistent with the experimentally observed trends. These results underscore the need for a d-orbital semiempirical representation for phosphorus and sulfur for the study of experimentally observed thio effects in enzymatic and nonenzymatic phosphoryl transfer reactions. One of the major advantages of the present approach is that it can be applied to model chemical reactions at a significantly lower computational cost than either the density-functional calculations with implicit solvation or the semiempirical QM/MM simulations with explicit solvent.