Since the introduction of the QM/MM approach by Warshel and Levitt in 1976 it has evolved to a broadly used tool in computational chemistry. Dividing a large biomolecular system into two subsystems, one smaller subsystem treated quantum-mechanically (QM) and one larger subsystem treated with molecular mechanics (MM), allows one to investigate the mechanisms and energetics of enzymatic reactions in an efficient way. Consequently, the application of the QM/MM approach to large biomolecules such as enzymes has become a common practice in the last two decades. However, in practice setting up QM/MM calculations is far from trivial and requires many manual choices by the simulation scientist. Besides the selection of a suitable QM method and an MM force field, the most important decision is the choice of the QM region.