Fragment-based screening (FBS) has become a common hit-finding approach for drug discovery. Small and well-characterized fragment libraries typically deliver higher hit rates of ligands with lower molecular weight and higher solubility than those derived from high-throughput screening approaches, making FBS an attractive technology. Since the inception of fragment-based technology in medicinal chemistry, nuclear magnetic resonance (NMR) methods have played, and continue to play, a significant role in the screening of fragments. A particularly attractive ligand-observed NMR technique uses 19 F as the NMR active isotope. This method known as FAXS is very sensitive to protein binding, uses low concentrations of fragments, and requires low amounts of unlabeled protein. It can screen and deconvolute large mixtures of compounds due to the wide range of 19 F NMR chemical shift, can identify reporter/spy molecules that can then be used to screen molecules not containing fluorine, and measure the binding affinity of the identified hits. The possibility of screening large mixtures makes 19 F NMR a high-throughput method.