Noroviruses are major causes of gastroenteritis, with epidemic outbreaks occurring frequently. They are an important global health concern, especially for pediatric and immunocompromised populations, and are challenging pathogens to target immunologically due to their rapid rates of genetic and antigenic evolution and failure to stimulate durable protective immunity. In this Review, we summarize our current understanding of norovirus pathogenesis, noting the prominent role of murine norovirus as a small animal model for norovirus research. We highlight intriguing data supporting the possible involvement of norovirus in sequelae including irritable bowel syndrome and inflammatory bowel diseases, and describe the innate and adaptive immune mechanisms involved in control of both human and murine norovirus infection. Furthermore, we discuss the potential implications of recent discoveries regarding norovirus interactions with the gut microbiota, and briefly detail current understanding of noroviral evolution and its influence on viral pathogenesis. Our mechanistic understanding of norovirus pathogenesis continues to improve with increasing availability of powerful model systems, which will ultimately facilitate development of effective preventive and therapeutic approaches for this pathogen.