The convergence of QM/MM results with the choice and particularly the size of the QM region has been investigated in several studies, which underline that it generally has a large effect on the quality of the final results, and that often rather large QM regions are required for reaching converged results. To alleviate this problem, schemes for the systematic construction of QM regions have been proposed, usually with the aim of obtaining medium-sized QM regions that provide reliable QM/MM reaction energies. Examples of such schemes include free energy perturbation analysis, 17 charge deletion analysis, charge shift analysis (CSA), and Fukui shift analysis (FSA). For their recently developed selfparametrizing system-focused atomistic models (SFAM), Brunken and Reiher proposed an automatic scheme for the construction of hybrid QM/SFAM models, including a systematic determination of the QM region based on the energy gradient. For a given QM region, there are different possible choices of the embedding method, of a suitable coupling scheme, and for the treatment of the boundary region if covalent bonds cross the border between the subsystems. For the commonly used electrostatic embedding scheme, the choice of the MM point charges will influence the resulting QM and QM/MM energies, and further parameters need to be chosen in advanced polarizable embedding or flexible embedding schemes. Different coupling schemes are available such as IMOMM, ONIOM, or the AddRemove 30 model. The most common approach for treating covalent bonds across the QM-MM boundary is saturating the QM region with capping atoms. Here, the position and the type of these atoms is crucial for the calculations. An alternative are frozen orbitals, 31 e.g., in the Localized SCF (LSCF) or the Generalized Hybrid Orbital (GHO) approach. The uncertainties introduced by all these different choices and the corresponding parameters are interconnected and will again depend on the choice of the QM region.