Theoretical treatments have been widely used over recent years for the investigation and development of molecularly imprinted materials, in particular for improving our understanding of the molecular mechanisms underlying the nature of the recognition events involved in the synthesis of MIPs and of MIP–ligand interactions. This chapter aims to present the different types of theory-based calculations—from quantum mechanical (QM) to semiempirical methods, followed by classical molecular dynamics (MD). The first section introduces the advantages and disadvantages imposed by each method, the second focuses on QM and MD techniques, alongside hybrid approaches for template optimization, while the third part outlines the optimization/investigation methods used for functional monomer selection. The T-FM interactions with cross-linking and porogenic agents are also considered. The final part of the chapter is focused on additional computational approaches for studying MIP systems, including binding energy calculations, structural and dynamical measurements, multivariate descriptors, and chemometric models. Finally, general conclusions and future prospects for the use of theoretical methods in the study and development of MIPs are presented.