Generating a large population of memory CD8 T cells is an appealing goal for vaccine design against a variety of human diseases. Indeed, experimental models have demonstrated that the overall number of memory CD8 T cells present at the time of infection correlates strongly with the ability to confer host protection against a range of different pathogens. Currently, the most conceivable approach to rapidly generate a large population of memory CD8 T cells is through the use of prime-boost vaccination. In addition, recent experimental findings have uncovered important principles that govern both the rate and magnitude of memory CD8 T cell formation. Thus, this has resulted in novel prime-boost vaccination strategies that could potentially be used in humans to generate protective populations of memory CD8 T cells.