A major challenge for immunologists has been the development of vaccines designed to emphasize cellular immune responses. One particularly promising approach is the prime-boost strategy, which has been shown to generate high levels of T-cell memory in animal models. Recently, several papers have highlighted the power of prime-boost strategies in eliciting protective cellular immunity to a variety of pathogens and have demonstrated efficacy in humans. Coupled with recent advances in our understanding of the mechanisms underlying the generation, maintenance and recall of T-cell memory, the field is poised to make tremendous progress. This Review discusses the impact of these recent developments on the future of prime-boost vaccine strategies.