Immunizations ranked among the greatest public health accomplishments during the 20th century in the United States. 11,12 Advances in biotechnology offer substantial promises in additional disease control through new vaccines, 36 especially when combined with new funding mechanisms for the developing world. 66 Increasing public concern about vaccine risks and vaccine safety, both real and perceived, however, has cast a shadow over these achievements and possibilities (Fig. 1). Vaccines are being linked to diseases ranging from autism to multiple sclerosis. 45,96 In an era of virtual eradication of vaccine-preventable diseases (VPDs) (Table 1), such safety concerns make it increasingly difficult to convince the populace to accept immunizations, raising the spectre of resurgence of VPDs. 41 Aside from smallpox and polio, however, few other VPDs are likely to be eradicated globally in the near future. The continued control of VPDs generally will require continued immunizations at as high a coverage as possible. To make this possible, a greater investment is needed in the scientific study of these purported vaccine risks to identify which are truly attributable to vaccines. 26 Should such an attribution be established, then further research is needed to identify the magnitude of the risk, the risk factors, the pathophysiology, and, hopefully, a safer vaccine. 27 This article reviews methods used to understand vaccine safety better and summarize recent developments and controversies (Table 2).