Annual use of influenza vaccines represents the largest vaccine campaign conducted in the USA. Recent expansions in influenza vaccine recommendations suggest a move toward ‘universal’ vaccination strategies. Although a great deal of safety data has been accumulated, concerns remain regarding rare, serious adverse events following immunization. A proven association between the 1976–1977 swine influenza vaccine and Guillain–Barré syndrome halted that particular national vaccination campaign. Recently, annual influenza vaccines have been associated with novel adverse events, for example, oculorespiratory syndrome in Canada. Any vaccine used against an influenza strain of pandemic potential will have an incompletely described safety profile. Thus, the challenge of influenza vaccine safety is to detect new safety concerns that may arise during seasonal campaigns, while preparing vaccine safety systems for the timely detection of adverse events in the setting of a pandemic.