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Considerable developments have been observed in fragment-based lead/drug discovery (FBLD/FBDD) recently, with four drugs approved and many others under investigation. Nuclear magnetic resonance (NMR) has gained increasing popularity in FBLD due to its intrinsic capability in characterizing protein-ligand interactions in a large dynamic range of affinity, from weak hits to highly potent drugs. Here, we summarize NMR applications in fragment-based hit-to-lead evolution, including the construction of a fragment library, screening methods, spectra processing, and the delineation of the protein-ligand binding modes. These state-of-the-art NMR techniques have been exemplified in the discovery of inhibitors against multiple targets over the past five years, and they are expected to continue to provide new insights in the future.