Due to their computational efficiency, empirical force fields play an indispensable role in computational chemistry, particularly in biomolecular simulations and computer-aided drug design. The traditional empirical force field approach assigns atom types based on an atom's bonding pattern and chemical element and represents the potential energy surface with atom-type-specific bonded harmonic terms for bonds, angles and torsions as well as non-bonded Lennard-Jones and Coulomb terms. Typically, the parameters are fitted to reproduce experimentally observed structural, dynamical and electrostatic properties or data from higher-level electronic structure calculations, for example, partial charges, torsional profiles and vibrational spectra of small molecules. One important application of empirical force fields is free energy calculations of protein-ligand interactions. Protein structure descriptions are generally reliable and transferable, because of small bond length and angle deviations from typical values over the course of a simulation and due to the well-defined chemical space of canonical amino acids, which exhibit conserved structures among the majority of studied proteins. However, the chemical space of drug-like molecules is consid-erably more complex and the range of reasonably low energy conformations is wider . As a consequence, the existing small molecule force fields are typically trained on only a fraction of the compounds needed for transferability. As a result, the aforementioned parameters, such as bond-spring constants, need to be fine-tuned for the force field to accurately represent the potential energy surface and interactions of the particular small molecule of interest in applications that require higher accuracy, such as binding free energy calculations. Another application of empirical force fields is conformational analysis, for assessment of the lowest energy and most relevant conformers of small molecules. In this application, empirical force fields are mainly used as initial structure generation tools, with subsequent refinement needed by semi-empirical or ab initio methods. Empirical force field-based conformational searching also plays a significant role in modelling organic reaction mechanisms, even though they are not designed to describe non-equilibrium structures and substantial modifications are necessary if reactivity is to be modelled. To further refine the structures and investigate reactions, ab initio methods are necessary, as with conformational searches. Although ab initio methods offer a significant improvement in accuracy over empirical force fields and allow to study reactive systems, they are mostly too computationally expensive for routine use in, for example, high-throughput virtual screening (e.g. 100s to 1000s of molecules processed in a span of hours) or routine molecular dynamics simulations of systems with 1000s of atoms.