The binding affinity of a drug to its target is an important quantity in early-stage drug discovery. Its quick and accurate prediction would allow the wasteful synthesis of weaklybinding molecules to be avoided. Substantial progress has been made towards this goal, with rigorous "alchemical" free energy calculations based on molecular dynamics or Monte Carlo sampling recommended as the optimal method. Alchemical relative binding free energy (RBFE) calculations, which evaluate the relative difference in binding affinity between structurally related molecules, are now routinely applied in the hit-to-lead and lead optimisation stages of drug discovery. However, standard RBFE calculations are limited to structurally similar molecules binding to the same target with the same binding mode. Alchemical absolute binding free energy (ABFE) calculations escape these constraints through their more general formulation. RBFE calculations are based on a thermodynamic cycle where two ligands are inter-converted in solution and while bound to their target; ABFE calculations involve removing a single ligand's intermolecular interactions in both environments. This makes ABFE calculations applicable to a wider class of problems, including accurately ranking diverse molecules in the final stages of high-throughput virtual screening. Unfortunately, the application of ABFE calculations is limited by their high computational cost. ABFE calculations require a relatively large modification of the system (complete removal of ligand intermolecular interactions) which increases the thermodynamic length around an ABFE cycle compared to an RBFE cycle. This necessitates more sampling for a result of equal precision. ABFE calculations are also particularly susceptible to sampling issues such as slow rehydration of the binding site and side-chain rearrangement. Calculating the relative binding free energy between a pair of similar ligands using a default ABFE protocol would be around an order of magnitude more expensive than with a default RBFE protocol, and would likely be less precise.