This chapter provides an overview of some of the different methods available for calculation of nuclear quantum effects in enzyme systems. A variety of different approaches are covered, including semiclassical, wavefunction and path integral-based methods. The chapter presents the application of these methods to the widely studied enzyme dihydrofolate reductase (DHFR). We compare the performance of the different methods in computing rate constants, tunnelling effects, donor–acceptor distances at transition states, and kinetic isotope effects. It is encouraging to see that very different approaches for including nuclear quantum effects, using different potential energy surfaces, and that are implemented in different software packages, give consistent results. Yet challenges still persist, particularly in the area of temperature-dependent kinetic isotope effects, which are particularly difficult to predict accurately.