The association between molecular size and risk of failure has promoted the use of binding efficiency as a prioritization metric in lead selection. Even though by extension it is often referred to as "ligand efficiency", the concept was originally conceived to be strictly applicable to comparing the binding efficiencies of ligands for a single target. With current trends in designing drugs to bind efficiently to multiple targets, a revision of the original binding efficiency definition is carried out. To this aim, the dependency of binding efficiency on polypharmacology is highlighted in a retrospective analysis of a set of antipsychotic drugs. Statistical standardization of target binding efficiencies relative to basal values obtained from a large background of medicinal chemistry compounds is proposed as a means to conciliate the concepts of binding efficiency and polypharmacology. Finally, the interplay between binding efficiency and therapeutic efficacy for optimizing natural products, random hits, and fragments is discussed.