Noroviruses are the most common cause of food-borne gastroenteritis worldwide, and explosive outbreaks frequently occur in community settings, where the virus can immobilize large numbers of infected individuals for 24-48 hours, making the development of effective vaccines and antiviral therapies a priority. However, several challenges have hampered therapeutic design, including: the limitations of cell culture and small-animal model systems; the complex effects of host pre-exposure histories; differential host susceptibility, which is correlated with blood group and secretor status; and the evolution of novel immune escape variants. In this Review, we discuss the molecular and structural mechanisms that facilitate the persistence of noroviruses in human populations.