Molecular replacement in X-ray crystallography is the prime method for establishing structure-activity relationships of pharmaceutically relevant molecules. Such an approach is not available for NMR. Here, we establish a comparable method, called NMR molecular replacement (NMR²). The method requires experimentally measured ligand intramolecular NOEs and ligand-protein intermolecular NOEs as well as a previously known receptor structure or model. Our findings demonstrate that NMR² may open a new avenue for the fast and robust determination of the interaction site of ligand-protein complexes at atomic resolution.