A new paradigm of rotavirus disease is emerging and rotavirus infection is no longer considered to be localized and confined to the GI tract. New evidence indicates that rotavirus infection is systemic. Viral antigen and infectious virus frequently enter the circulation in both children and animal model systems. Clinical case reports of systemic sequelae to rotavirus infection in children continue to accumulate, suggesting involvement in systemic disease syndromes. The use of animal models is providing biological and molecular evidence for infection at peripheral sites. Thus, infection at peripheral sites may account for reports of systemic sequelae to rotavirus infection. The importance of systemic sequelae and the ability of vaccination to prevent such sequelae remains to be determined.