Rotaviruses cause life-threatening gastroenteritis in children worldwide; the enormous disease burden has focused efforts to develop vaccines and led to the discovery of novel mechanisms of gastrointestinal virus pathogenesis and host responses to infection. Two live-attenuated vaccines for gastroenteritis (Rotateq [Merck] and Rotarix) have been licensed in many countries. This review summarizes the latest data on these vaccines, their effectiveness, and challenges to global vaccination. Recent insights into rotavirus pathogenesis also are discussed, including information on extraintestinal infection, viral antagonists of the interferon response, and the first described viral enterotoxin. Rotavirus-induced diarrhea now is considered to be a disease that can be prevented through vaccination, although there are many challenges to achieving global effectiveness. Molecular biology studies of rotavirus replication and pathogenesis have identified unique viral targets that might be useful in developing therapies for immunocompromised children with chronic infections.