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Noroviruses (NoVs), members of the Calicivirus family, are small, positive-polarity RNA viruses and the most important cause of human foodborne viral gastroenteritis worldwide. These viruses cause gastrointestinal disease, resulting in recurrent bouts of vomiting and diarrhea that typically last 24–48 hours. NoVs are transmitted via the fecal–oral route, most commonly through infected food or water or person-to-person contact, and result in 267 million infections [1] and over 200,000 deaths each year, mostly in infants and the elderly [2]. Vaccines and therapeutics are under development but face considerable challenges as there is no cell-culture system or small-animal model for human disease, and these viruses are highly heterogeneous and undergo antigenic variation in response to human herd immunity, further complicating our understanding of the complex immune interactions that regulate susceptibility and disease. Despite these limitations, considerable progress has been made in understanding NoV adaptive immunity. This article discusses our current understanding of virus–host immune interactions that regulate host susceptibility, virus evolution, and protective immunity. We focus on virion structure, serologic relationships among strains, molecular mechanisms governing the changing antigenic landscape of human NoVs over time, cellular immunity, and relationships between human herd immunity, antigenic variation, and histoblood group antigen (HBGA) recognition, which are predicted to drive the emergence of new outbreak strains that target different human populations and/or afford escape from protective herd immunity. We …