Enzymes are remarkably efficient catalysts evolved to perform well-defined and highly specific chemical transformations. Studying the nature of enzymatic rate enhancements is highly important from several aspects, including the rational design of synthetic catalysts and transition-state inhibitors. Herein, we describe recent progress in our group in the development of multiscale simulation methods and their application to several enzyme systems. In particular, we describe the use of combined quantum mechanics/molecular mechanics (QM/MM) methods in classical and quantum simulations. The development of various novel path-integral methods is reviewed. These methods are tailor-made for enzyme systems, where only a few degrees of freedom involved in the chemistry need to be quantized. The application of the hybrid QM/MM quantum-classical simulation approach to three case studies is presented. The first case involves proton transfer in nitroalkane oxidase, where the enzyme employs tunneling as a catalytic fine-tuning tool. The second case presented involves orotidine 5′-monophosphate decarboxylase, where multidimensional free energy simulations together with kinetic isotope effects are combined in the study of the reaction mechanism. Finally, we discuss the monoterpene cyclase bornyl diphosphate synthase, where non-statistical dynamics is a key component in enzyme function.