Memory CD8 T cells play a critical role in providing protection to immune hosts by orchestrating rapid elimination of pathogen-infected cells after re-infection. Systemic bacterial infection with Listeria monocytogenes has been a favored approach for researchers to characterize pathogen-specific CD8 T cell responses, and in-depth understanding of L. monocytogenes biology has provided invaluable experimental tools that have been used to increase our understanding of memory CD8 T cell differentiation. Here, we describe how the tools from this murine model system of infection have been utilized to characterize pathogen-specific CD8 T cells in inbred and genetically diverse outbred hosts as they undergo naïve-to-memory CD8 T cell differentiation in vivo. We also discuss how studying L. monocytogenes-evoked CD8 T cell responses have provided insight on the degree of diminished T cell immunity in clinically relevant conditions such as sepsis and obesity. Overall, this review will highlight how infection with the intracellular pathogen L. monocytogenes has enabled analysis of systemic CD8 T cell responses and greatly contributed to what is known about memory CD8 T cell generation and differentiation.