Specific interactions between proteins are a fundamental process underlying the various biological events, such as cell–cell contacts, signal transduction, and gene expression. Therefore, the structural investigations of protein–protein interactions provide useful information for understanding these events. We describe an NMR method, termed the cross-saturation (CS) method, to determine the binding sites of protein complexes more precisely than conventional NMR methods. The CS method can determine the binding sites of a protein complex that undergoes fast exchange between the free and the bound states, regardless of the molecular size of the complex.