The in silico prediction of protein-ligand binding affinities is an important problem in drug discovery. The ability to rapidly and accurately calculate affinities for arbitrary proteinligand systems would allow the efficient prioritisation of compounds for synthesis and testing, accelerating the hit-to-lead and lead optimisation stages of drug discovery. Recent improvements in computing power and automation have brought this vision closer to realisation. In particular, alchemical methods are ideally suited for application during the hit-to-lead and lead optimisation stages of drug discovery, as well as in the later stages of virtual screening. Along with path-based methods, alchemical simulations form a class of exact (in the limit of complete sampling and a perfect description of the potential energy) methods based on molecular dynamics or Monte Carlo sampling which provide binding affinity predictions of greater accuracy than alternatives. Modern computing resources now support routine use of alchemical relative binding free energy (RBFE) calculations to add value during drug discovery campaigns. RBFE calculations avoid the computationally intractable challenge of converging unbiased simulations of ligand binding and unbinding by instead gradually interconverting two structurally similar ligands. Interconversion proceeds through unphysical "alchemical" inter-mediates and is done in both the bound and unbound states. Based on a thermodynamic cycle, the free energy differences for each step are summed to yield the difference in the free energy of binding between the ligands. RBFE calculations are used routinely and protocols for their robust deployment have been researched in detail. However, as a result of the requirement for a common ligand core, binding pose, and binding site, the following valuable problems typically lie outside the scope of RBFE calculations: 1. Calculating the RBFEs of structurally dissimilar ligands to a common target 2. Calculating RBFEs of the same ligand to the same protein with different binding poses 3. Calculating the RBFEs of the same ligand to different targets 4. Calculating the absolute binding free energy of a given ligand to a given target Alchemical absolute binding free energy (ABFE) calculations escape these limitations by following a more general thermodynamic cycle in which the ligand's intermolecular interactions are completely turned off. In principle, these calculations can be used to calculate the binding free energies of structurally diverse molecules to varied targets, making them attractive for drug discovery. However, the alchemical ABFE framework presents challenges not encountered during an RBFE calculation. Restraints must be applied between the protein and ligand to avoid convergence issues such as those associated with the ligand "wandering" out of the binding site as its intermolecular interactions are removed. Restraints may also be required to avoid errors in the calculated binding free energies when the bound state is implicitly defined to include configurations where the ligand is anywhere in the entire simulation box relative to the receptor, as is the case when restraints are not used. However, these errors only affect weak binders (Section S1).