Noroviruses (NV) are non-enveloped, single-stranded, positive-sense RNA viruses that are the major cause of epidemic outbreaks of gastroenteritis worldwide [273,274,275]. The viral coat consists of a single protein, VP1, which assembles into a capsid with overall icosahedral symmetry [276,277,278]. Attachment of human noroviruses to histo-blood group antigens (HBGAs) is thought to be critical for the infection process [279]. The protruding domains of the VP1 proteins, called P-domains, harbor highly conserved binding sites for HBGAs. STD NMR-based epitope mapping was used [262,271] to identify structural features of different core types critical for the binding of synthetic A- and B-tetrasaccharides [280] to virus-like particles (VLPs) of a highly homologous GII.4 strain (Ast6139). STD NMR experiments provide a robust and straightforward technique for obtaining ligand binding epitopes at atomic resolution. Comparing binding epitopes of related ligands then delivers critical information about structural requirements for ligand recognition. Conversely, comparison of binding epitopes of a given ligand binding to wild type, and to mutant proteins reveals the importance of individual amino acids for binding. STD NMR experiments with L-Fuc and B-trisaccharide in the presence of wild type and mutant VLPs yield virtually identical binding epitopes and suggest that these two mutations do not significantly alter HBGA recognition. The STD NMR approach to characterize binding of HBGA ligands to noroviruses has employed VLPs as targets and thus taken advantage of the large size of VLPs yielding excellent signal-to-noise ratios of the corresponding STD NMR spectra, as demonstrated previously [281].