Vaccines are lifesaving interventions that reduce the morbidity and mortality of disease. Fortunately, serious adverse events with vaccination are uncommon, but they must promptly be recognized and evaluated to assess and clarify the safety of future administration, a process that the public must understand in order to feel safe in receiving vaccines. In this article, we provide a review of vaccine development, discuss the process by which safety is ensured, and describe key adverse events associated with their administration. We review in detail existing mechanisms for reporting these events and assessing them following recovery, as well as communication related to vaccine safety. We also describe barriers to vaccination, such as nocebo effects and antivaccination groups, and use lessons learned from the successful development of COVID-19 vaccines during the recent pandemic to define future opportunities and directions for vaccine safety.