The first candidate rotavirus vaccine was a live attenuated oral vaccine made by the classical empirical method of serial passage of virus in tissue culture cells. Current tetravalent vaccine candidates that are in the final stages of efficacy testing in the United States were made by genetic reassortment. This article briefly highlights how advances in the basic understanding of the molecular biology of rotaviruses have facilitated vaccine development. New approaches for second-generation vaccines and improvements in vaccine efficacy based on further exploitation of the tools and knowledge of rotavirus molecular biology and pathogenesis are discussed.