Alchemical Free Energy (AFE) calculations have seen significant increase in popularity in both the academic and commercial domains of pharmaceutical development. These types of calculations leverage an alchemical description of a molecular perturbation for the purpose of estimating free energies of binding of ligands to a drug target. Absolute Binding Free Energy (ABFE) calculations are not yet routinely used for protein-ligand systems owing to challenges in converging accurate free energy estimates. As a result relative binding free energy (RBFE) calculations remain one of the most popular types of AFE techniques, and have become pivotal in modern computational chemistry approaches that support medicinal chemistry campaigns. Its success is largely owed to recent improvements in processing hardware coupled with advances in empirical force fields which has pushed the technique's potential to predict ligand binding affinities with a mean unsigned error below 1 kcal•mol -1 , at acceptable computational costs. The field of RBFE calculations has seen considerable progress over the last several years with both academic and commercial developers pushing its boundaries even further using a variety of community-curated benchmarking series and guidelines. The community's performance across the available RBFE benchmarking sets is variable due to the heterogeneity of RBFE implementations. This variability is primarily explained by limitations in used RBFE software. This results in bottlenecks that can be shared across RBFE software, such as inaccuracies when performa EaStCHEM School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, United Kingdom. E-mail: julien.michel@ed.ac.uk b Cresset Group, New Cambridge House, Bassingbourn Road, Litlington, Cambridgeshire, SG8 0SS, United Kingdom.