Despite recent advances in methodologies that better characterize local water structure and thermodynamics, the simply- stated question of whether it would be beneficial or detrimental, in a free-energetic sense, to displace water from a region of a protein with a suitably complementary ligand continues to be a conundrum. Solvation thermodynamic mapping techniques have provided valuable insight into the role of displacing water in molecular recognition however solvation thermodynamics alone is not predictive of displaceability and tightly binding ligands regularly displace water from both regions that are characterized as having favorable solvation and regions that are characterized as having unfavorable solvation. Part of the difficulty of assessing the thermodynamics of water displacement is due to the large number of often counteracting contributions and the consequent lack of a simplifying conceptual framework. We will discuss the key insights which have been gained from solvation thermodynamic mapping and how we are incorporating them into drug discovery and design methodologies. We will also discuss remaining issues on predicting favorability of water displacement and suggest how they might be tackled.