Drug discovery is a challenging endeavor with a high failure rate. This is further complicated by the fact that each disease has its own unique set of obstacles to developing a safe and effective therapy. Flexible and robust analytical methods are critical for efficiently solving these issues, where nuclear magnetic resonance (NMR) plays an important role in nearly every stage of the drug discovery process. This review will highlight recent developments in the application of NMR as a screening tool for drug discovery that includes: library design, various ligand-affinity screening techniques, rapid determination of protein-ligand co-structures, and the functional annotation of proteins to the discovery of new therapeutic targets.