Nuclear magnetic resonance (NMR) has evolved into a powerful tool for characterizing protein-ligand interactions in solution under near physiological conditions. It is now frequently harnessed to assess the affinity and specificity of interactions; to identify binding epitopes on proteins and ligands; and to characterize the structural rearrangements induced by binding.The first section of this chapter provides a general overview of the NMR study of protein-ligand interactions. The section is divided according to two main categories of experiments: those based on observing protein signals and those based on observing ligand signals. The next section explains two case studies performed in the authors' laboratory. The first of these deals with the interaction between vascular endothelial growth factor and a peptidic ligand, and includes a detailed protocol of chemical shift perturbation experiments. The second one reports on the interaction between prolyl oligopeptidase and a small molecule as monitored by ligand saturation transfer difference (STD), and illustrates how NMR can be used to confirm binding and to identify the binding epitope of a ligand.