In 1998, a simian-human reassortant rotavirus vaccine was licensed and recommended for routine use in children. Within 1 year, however, the vaccine was found to be a cause of intussusception, estimated to be approximately 1 case per 10,000 immunized children, and the recommendations were withdrawn. Although the etiology and pathogenesis of vaccine-associated intussusception remain unclear, immunologic studies suggest several hypotheses. Development of new rotavirus vaccines necessitates the need for large, prelicensure, clinical trials to determine safety. Candidate vaccines currently in clinical trials include a bovine-human reassortant pentavalent vaccine and an attenuated human rotavirus monovalent vaccine. Important issues to be addressed include the acceptable, if any, degree of risk of developing intussusception and economic issues concerning the distribution of the vaccine in developing countries. The continuing interest of pharmaceutical companies in developing a safe and effective vaccine is encouraging, especially given the enormous burden of rotavirus disease in developing countries.