Fragment-based drug discovery (FBDD) is becoming increasingly popular in industry to identify hits in the early stages of a drug discovery program, with 180 fragment-to-lead studies published between 2015 and 2022, and 7% of all clinical candidates published in the Journal of Medicinal Chemistry between 2018 and 2021 originating from a fragment screen. Fundamental to FBDD is screening small libraries of diverse fragment molecules optimized to cover a large portion of chemical space. Typically, fragment libraries generate more, but less potent, hits compared to libraries of larger, more complex, molecules. Although fragment hits tend to be weak binders, they generally provide a more useful starting point for hit-to-lead optimization compared to larger drug-like molecules owing to their simplicity, lack of molecular obesity, rigidity, and numerous potential growth vectors. Owing to their small size, fragments have very low binding affinities with dissociation constants (K D ) typically in the millimolar range. Even with specialized biophysical techniques, these binding events are difficult, and sometimes impossible, to detect. X-ray crystallography (XRC) can serve as hit detection while also providing a detailed structural picture of fragment binding. However screening by XRC requires a reliable, high-throughput, and system-agnostic method of producing high quality crystals of protein-ligand complexes. Unfortunately, for some protein targets (e.g. membrane and disordered proteins), producing such crystals can be difficult and costly. Furthermore, resolving the binding modes of small fragments can be tricky owing to unclear electron density, particularly for molecules with a high degree of symmetry or disorder. Finally, XRC does not provide any information on how tightly a molecule is bound to a target, although one could, in principle, infer a limit for the binding affinity from the crystallization conditions. Binding affinity data is desirable in drug discovery campaigns to rank hits based on how strongly they interact with a target, thus providing an additional critical component in deciding which fragments are the most promising for development.