As immunization programs world-wide "mature" with high vaccine coverage and near elimination of vaccine-preventable disease, vaccine safety issues have increased in relative prominence. In the wake of events of 11 September 2001, fear of bioterrorism has reemerged. The paradigm of eradicating vaccine-preventable diseases, stopping vaccinations and thereby also eradicating the associated vaccine adverse events (a la smallpox) may unfortunately be obsolete. If all vaccinations have to be continued indefinitely, research is needed more than ever to understand and prevent rare vaccine adverse events. Case-control studies are usually best suited for such purposes, especially when nested within a pre-existing large-linked administrative database cohort to minimize bias. The new clinical immunization safety assessment centers may play an important role in bridging the sometimes conflicting clinical and epidemiologic perspectives in vaccine safety.