Noroviruses are recognized as a leading cause of viral foodborne gastroenteritis. With the successful vaccination program being developed against rotavirus, focus is shifting to norovirus as the primary causative agent of severe childhood diarrhea resulting in a yearly estimate of 1.1 million episodes of pediatric gastroenteritis in developed nations and 218,000 deaths in developing nations [9] . The elderly and immunocompromised also suffer sometimes life-threatening or chronic long-term norovirus diarrheal disease characterized by malnutrition and dehydration [48] . In some HIV infected patients, chronic norovirus diarrheal disease is associated with persistent norovirus infection [49] . The economic disease burden of a norovirus outbreak within a care facility has been estimated at over $657,000 for a single event [50] . These statistics emphasize the critical need for a norovirus vaccine. Although recent reports strongly support the development and use of an efficacious norovirus vaccine in humans [38, 51] , a primary obstacle to a successful vaccine is the lack of a definitive correlate to protection coupled with the extreme antigenic variation across the many norovirus strains. In fact, the existence of long-term protective immunity to norovirus infection remains controversial within the field [52] . Human challenge studies conducted before molecular diagnostics of infection and refined immune response assays had indicated that some volunteers could be reinfected with the same norovirus strain, suggesting that norovirus infection did not induce long-term protection [53] . However, recent reports identifying immune responses in norovirus-challenged but uninfected volunteers [44, 54] have necessitated qualification of these early observations to acknowledge that the findings may be compromised by assay limitations and/or the overwhelming challenge dose in comparison to the very low norovirus infectious dose [44, 54] . Clearly defining the relationships between pre-exposure history, blockade antibody responses, T cell immunity, virus evolution, and the components of protective immunity represent key challenges for future vaccine and therapeutic design.