Rotavirus is the most common cause of acute infectious gastroenteritis in children and is associated with substantial morbidity in the United States and morbidity and mortality in the developing world. Two orally administered vaccines, a live bovine reassortant vaccine (RV5; licensed in 2006) and a live attenuated human vaccine (RV1; licensed in 2008), are now being used in a universal infant vaccination program in the United States. There is already ecologic evidence and data from post-licensure effectiveness studies that this program will be an unequivocal success in reducing the impact of rotavirus disease. This overview presents the structure, pathogenesis, and mechanisms of natural immunity to rotavirus, key concepts in understanding the rationale behind vaccine-induced protection. The history of rotavirus vaccine development is also included, along with a discussion of the safety, efficacy, and recommended use of the approved vaccines.