Vaccines have contributed enormously in reducing the impact of many infectious diseases, and the expanded use of new and existing vaccines provides unprecedented potential for further reducing the global burden of infectious diseases. Yet, as with the deployment of other technologies, their use may also sometimes be associated with undesirable effects that need to be identified rapidly, understood and minimized. In this article, we review the models and systems that have been developed to monitor and respond to concerns regarding vaccine safety and we give illustrative examples of real or perceived vaccine safety issues. The Global Advisory Committee on Vaccine Safety (GACVS) was set up 10 years ago and charged to provide the WHO with independent advice on vaccine safety issues. The role of the GACVS is both to analyze and to interpret reports of the adverse effects of vaccines that impact on global vaccination programs and strategies, and to foster the development of improved surveillance systems to detect any adverse effects of vaccines, particularly in low- and middle-income countries. It also monitors the development of new vaccines during clinical testing and advises on the safe use of vaccines in immunization programs. As success is achieved with reducing the burden of vaccine-preventable diseases, there will be increasing attention focused on potential adverse effects, on the development of effective surveillance systems to detect adverse effects, and on improved methods to manage and control any harmful consequences of vaccination.