The association between the first oral rotavirus vaccine to be licensed in the U.S. (Rotashield) and intussusception has presented a major challenge to the effort to reduce the global burden related to rotavirus infection. Although the risk of developing intussusception following immunization with Rotashield is low, debate continues about the estimation of intussusception risk and the events surrounding the withdrawal of the vaccine. The experience with Rotashield has highlighted the wisdom of parallel clinical trials in developing and developed countries and the value of post-licensure surveillance for the detection of uncommon adverse events. This review retraces the steps leading up to the withdrawal of the Rotashield vaccine and reflects on how this experience has influenced the development of other rotavirus vaccines.