The yellow fever vaccine plays an essential role in protecting humans from yellow fever, and millions of doses are administered each year. The attenuated live-virus vaccine has long been considered to be among the safest and most effective vaccines. Newly recognized rare, but sometimes fatal, adverse events associated with the vaccine have prompted scrutiny of the traditional recommendations for use of the vaccine and have raised questions about their pathogenesis. This paper describes the adverse events associated with the vaccine, reviews postulated reasons for the recent recognition of these events, discusses key research questions that need to be addressed in trying to understand their origin and risk factors, and reviews current indications for the use of the vaccine. Knowledge of the epidemiology of yellow fever is necessary to make informed recommendations. Current surveillance is inadequate to provide a precise exposure risk for most travelers.