In addition to the clinical applications of therapy and diagnosis, monoclonal antibodies have also proven to be superior tools for studying viral antigenicity, evolution, and for the treatment of acute viral disease in humans [13, 34, 55, 56] . Characterization of neutralizing mAb escape-mutants has been fundamental to identifying epitopes associated with virus receptor usage, pathogenesis, and fitness [57] [58] [59] . In this manuscript, we isolated and characterized the first human mAbs against noroviruses, derived from a healthy donor whose pre-exposure history was unknown. The number of unique GII.4 human monoclonal antibodies in this patient accurately reflects the high prevalence of GII.4 norovirus infection seen in human populations over the past 25 years. Moreover, distinct antibody cross reactivity patterns support the hypothesis that the GII.4 genotype is undergoing antigenic variation which not only correlates with loss of antibody blockade activity and emergence of new epidemic norovirus strains, but also changing carbohydrate ligand binding patterns over time.