Trafficking of CD8 T cells, in both the steady-state and during episodes of infection or inflammation, is a highly dynamic process and involves a variety of receptor–ligand interactions. A thorough, mechanistic understanding of how this process is regulated could potentially lead to disease prevention strategies, through either enhancing (for infectious diseases or tumors) or limiting (for autoimmunity) recruitment of antigen-specific CD8 T cells to areas of tissue inflammation. As CD8 T cells transition from naive to effector to memory cells, changes in gene expression will ultimately dictate anatomical localization of these cells in vivo. In this article, we discuss recent advances in understanding how antigenic stimulation influences expression of various trafficking receptors and ligands, and how this determines the tissue localization of CD8 T cells.