The global implementation of rotavirus vaccines will result in a major step toward limiting the disease burden of rotavirus infection. However, as history has shown with the experience of Rotashield (Wyeth Lederle Vaccines), the introduction of a new vaccine should occur in parallel with a postmarketing surveillance strategy to detect any unexpected or rare adverse events. Two new rotavirus vaccines (Rotarix [GSK Biologicals] and RotaTeq [Merck]) have been found to be safe and effective in large clinical trials involving >60,000 infants in the Americas and Europe. However, given that intussusception is an extremely rare event, some risk could be detected as the vaccine is administered to a larger number of infants. In response to a recommendation of the World Health Organization Global Advisory Committee for Vaccine Safety, a standardized approach to the postmarketing surveillance of rotavirus vaccine safety has been developed. We review the principal safety issues requiring further evaluation in postlicensure use of rotavirus vaccines. For intussusception, we also discuss challenges and approaches to monitoring.