The 2017 Stanley A. Plotkin Lecture in Vaccinology was delivered by Professor Peter F. Wright at the Pediatric Academic Societies Annual Meeting in San Francisco, California, in May 2017. The presentation provided an overview of the mucosal immune system as it applies to vaccinology. Specifically, Professor Wright’s lecture highlighted the remarkable opportunities for mucosal immunity research afforded by having both topically administered live vaccines and systemically administered inactivated vaccines available for the same pathogen. Using influenza and poliovirus case studies, Professor Wright described the use of live attenuated vaccines for human challenges and discussed how recent technological advancements in immunological assays have ushered in a new era for investigating the correlates of immune protection against wild-type infections at mucosal sites.