Alchemical free energy calculations employ an unphysical path that connects two physical end states in order to obtain free energy differences. Let us consider for example the process of turning the interactions of a ligand off in the binding site. The initial state in this case is the fully interacting ligand bound to the protein and the final state is the decoupled ligand, not interacting with its surroundings, and a sepa-rate protein and solvent box. Here the unphysical path describes how the electrostatic and steric interactions between the ligand and the protein and surrounding solvent molecules are gradually turned off. The unphysical intermediates ensure sufficient overlap of phase space as the system is modified, allowing for calculation of accurate free energies. The Hamiltonian of the system is coupled to a parameter λ which controls the progress between the physical end states. λ can have discrete or continuous values between 0 (initial state) and 1 (final state) and the intermediate states are often referred to as λ windows. Different alchemical approaches have been developed, each having its strengths and weaknesses.