In the clinical development of a vaccine, an efficacy study asks the question, "Does the vaccine work?" In contrast, an effectiveness study asks the question "Does vaccination help people?". In general, vaccine development proceeds from a study of immunogenicity to a randomized controlled trial that determines vaccine efficacy under ideal conditions. Efficacy studies, however, have several limitations. In an immunogenicity study, when a vaccine is given according to different schedules, the object of the study is not the vaccine itself but the schedules; i.e., what is important is not the "relative immunogenicity" of the vaccine, but which schedule is more protective given the occurrence of the disease that is to be prevented. Furthermore, a clinical trial of vaccine efficacy is unable to predict accurately the level of protection that will be achieved in public health practice. Vaccination effectiveness can be evaluated in a prospective clinical trial, although few such studies have been undertaken. Effectiveness is usually assessed retrospectively, sometimes using a screening test, but more often in a case-control or cohort study. In these studies, rigorous risk adjustment is necessary to ensure the comparability of study populations. Retrospective studies also provide a means for assessing serious but rare vaccine-associated adverse events, an undertaking often needed to maintain public confidence in vaccination programmes. Many vaccines currently under development will be replacement rather than new vaccines, and they are unlikely to be evaluated in traditional efficacy trials. In future years, effectiveness studies, some of them using large administrative databases, will become increasingly important features of vaccine development and the formulation of public policy for immunization.