CD8 T cells are an important part of the adaptive immune system providing protection against intracellular bacteria, viruses, and protozoa. After infection and/or vaccination, increased numbers of antigen-specific CD8 T cells remain as a memory population that is capable of responding and providing enhanced protection during reinfection. Experimental studies indicate that while memory CD8 T cells can be maintained for great lengths of time, their properties change with time after infection and/or vaccination. However, the full scope of these changes and what effects they have on memory CD8 T cell function remain unknown. In addition, memory CD8 T cells can encounter antigen multiple times through either reinfection or prime-boost vaccine strategies designed to increase numbers of protective memory CD8 T cells. Importantly, recent studies suggest that memory CD8 T cell development following infection and/or vaccination is influenced by the number of times they have encountered cognate antigen. Since protection offered by memory CD8 T cells in response to infection depends on both the numbers and quality (functional characteristics) at the time of pathogen re-encounter, a thorough understanding of how time and antigen stimulation history impacts memory CD8 T cell properties is critical for the design of vaccines aimed at establishing populations of long-lived, protective memory CD8 T cells.