The success of immunizations in nearly eliminating many vaccine-preventable diseases has resulted in an increase in the need to study risks from vaccines, combination or otherwise. The well-known limitations associated with prelicensure trials have led many to hope that postlicensure studies can address safety issues. This article reviews measures that have been or should be taken to meet this expectation: establishment of clinical immunization safety assessment centers, standardization of case definitions for vaccine adverse events, use of the Vaccine Identification Standards Initiative to improve the accuracy and efficiency with which vaccination records are transferred, integration of vaccine safety monitoring into immunization registries, establishment (and enlargement) of the Vaccine Safety Datalink project, use of innovative analytic tools for better signal detection, and implementation of various methods to overcome confounding by contraindication. Only by investing in vaccine safety infrastructure at a level commensurate with investments in vaccine development can we hope to retain the public's confidence in immunization.