The article discusses the role of ligand efficiency measures in drug discovery, particularly in fragment selection, hit-to-lead optimization, and lead optimization. Ligand efficiency, such as binding free energy per heavy atom count (LE) and lipophilic ligand efficiency (LLE), quantifies the molecular properties required for binding affinity to a drug target. The application of these metrics has been widely reported in the selection and optimization of fragments, hits, and leads. Optimizing lipophilic ligand efficiency can increase affinity while reducing lipophilicity, even for challenging 'lipophile-preferring' targets. Mean ligand efficiency measures combined with drug-like physical properties can estimate target 'druggability.' An analysis of 480 target-assay pairs from the primary literature shows weak correlations between biological activity and physical properties, indicating that increasing activity does not always require improving physical properties. A study of 46 recently marketed oral drugs shows that they often have highly optimized ligand and lipophilic ligand efficiencies for their targets. Optimizing ligand efficiencies based on both molecular size and lipophilicity, in the context of specific targets, can help mitigate molecular inflation and improve the developability of drug candidates. The authors recommend using ligand efficiency metrics throughout drug discovery to guide the selection and optimization of compounds, emphasizing the importance of controlling lipophilicity and maintaining drug-like physical properties.The article discusses the role of ligand efficiency measures in drug discovery, particularly in fragment selection, hit-to-lead optimization, and lead optimization. Ligand efficiency, such as binding free energy per heavy atom count (LE) and lipophilic ligand efficiency (LLE), quantifies the molecular properties required for binding affinity to a drug target. The application of these metrics has been widely reported in the selection and optimization of fragments, hits, and leads. Optimizing lipophilic ligand efficiency can increase affinity while reducing lipophilicity, even for challenging 'lipophile-preferring' targets. Mean ligand efficiency measures combined with drug-like physical properties can estimate target 'druggability.' An analysis of 480 target-assay pairs from the primary literature shows weak correlations between biological activity and physical properties, indicating that increasing activity does not always require improving physical properties. A study of 46 recently marketed oral drugs shows that they often have highly optimized ligand and lipophilic ligand efficiencies for their targets. Optimizing ligand efficiencies based on both molecular size and lipophilicity, in the context of specific targets, can help mitigate molecular inflation and improve the developability of drug candidates. The authors recommend using ligand efficiency metrics throughout drug discovery to guide the selection and optimization of compounds, emphasizing the importance of controlling lipophilicity and maintaining drug-like physical properties.