It has been known for a long time that memory CD8+ T cells are the main players in conferring long-lasting and effective protection against infection with intracellular pathogens. The generation of instantly protective memory cells, so-called effector memory T cells, represents the basic principle of T cell-based vaccination strategies. Therefore, the understanding of the exact mechanisms required for in vivo generation of distinct CD8+ memory T cell subtypes will become the crucial rationale for enhancing the efficiency and quality of vaccine-induced protective immunity.