The development of vaccines to protect against viral disease is one of the hallmarks of modern medicine. The first vaccine was produced by Edward Jenner in 1796 in an attempt to provide protection against smallpox. Jenner theorized (correctly) that cowpox, a disease of animals, was similar to smallpox. He concluded that the human reaction to an injection of cowpox virus would somehow teach the human body to respond to both viruses, without causing major illness or death. Regulatory issues are involved in nearly every aspect of vaccine development, manufacturing, and marketing approval. Vaccine regulation began with a foundation on vaccine testing, and only in response to tragedies associated with vaccine use did new concepts begin to be defined. Vaccine regulation now includes a range of functions that cover the entire continuum of vaccine development and use. The future of effective regulation for vaccines that will allow innovation while protecting the public health must be based on three guiding principles: a firm science base for policies and decisions, a risk-based approach to implementation of regulatory oversight, and support for regulatory research to inform these activities.