The documented unfavorable changes of physicochemical properties during lead discovery and optimization prompted us to investigate the present practice of medicinal chemistry optimization from a thermodynamic perspective. Basic principles of binding thermodynamics suggest that discriminating between enthalpy-driven and entropy-driven optimizations could be beneficial. We hypothesize that entropy-driven optimizations might be responsible for the undesirable trend observed in physicochemical properties. Consequently, we suggest that enthalpydriven optimizations are preferred because they provide better quality compounds. Monitoring binding thermodynamics during optimization programs initiated from thermodynamically characterized hits or leads, therefore, could improve the success of discovery programs. Here, we summarize common industry practices for tackling optimization challenges and review how the assessment of binding thermodynamics could support medicinal chemistry efforts.