In the past decade, research has demonstrated that defectively packed hydrogen bonds, or "dehydrons," play an important role in protein-ligand interactions and a host of other biochemical phenomena. These results are due in large part to the development of computational techniques to identify and analyze the hydrophobic microenvironments surrounding hydrogen bonds in protein structures. Here, we provide an introduction to the dehydron and the computational techniques that have been used to uncover its biological and biomedical significance. We then illustrate how dehydron-based computational analysis can be used as a basis for reengineering pharmaceutical compounds to improve their binding specificities.