NMR has a long history in drug discovery and hit-to-lead optimization. Compared to many other methods NMR has the advantage of combining structural and functional parameters to characterize protein inhibitor interactions. NMR methods used in this context can be split into two categories; protein based experiments using isotopically labelled protein samples and a broad range of ligand based methods. Recently, there has been a strong emphasis on so-called ligand-based methods which offer a broad range of options to determine binding epitopes. Ligand-based methods are attractive because they are broadly applicable, impose few constraints on the composition of the target protein and don't require isotopic labeling of the protein or ligands. Such experiments include diffusion experiments, saturation transfer difference (STD-NMR), NOE pumping, waterLOGSY, SALMON, transferred-NOE and INPHARMA. Ligand-based NMR methods have been employed in screening and in lead optimization. One key advantage arises from their capability to pick up specific interactions for compounds of relatively low affinity and their ability to provide limited structural information without any need of crystallization or isotopic labeling.