The intracellular interactions of biomolecules can be maneuvered to redirect signaling, reprogram the cell cycle, or decrease infectivity using only a few dozen atoms. Such "molecular glues," which can drive both novel and known interactions between protein partners, represent an enticing therapeutic strategy. Here, we review the methods and approaches that have led to the identification of small-molecule molecular glues. We first classify current FDA-approved molecular glues to facilitate the selection of discovery methods. We then survey two broad discovery method strategies, where we highlight the importance of factors such as experimental conditions, software packages, and genetic tools for success. We hope that this curation of methodologies for directed discovery will inspire diverse research efforts targeting a multitude of human diseases.