Owing to their limited proliferative capacity and poor long-term survival, the CD27lowKLRG1hi subset of effector memory CD8+ T cells was assumed to have a small role in protection against secondary infections. Now, it has been shown that these cells in fact have a potent cytotoxic capacity and a distinct localization in the red pulp of the spleen, where they provide effective protection against secondary challenge with Listeria monocytogenes or vaccinia virus. The KLRG1hi population form the main secondary memory cell subset following antigen-specific boosting and are optimally placed to engage with invading pathogens. This study suggests that the composition and the location of CD8+ T cell populations might be the best predictors of vaccine efficacy.