Immune responses to infection or effective vaccination generally result in the development of memory lymphocytes capable of mounting a rapid response to secondary infection. Since most infections initiate in non-lymphoid tissues, defense at these sites may be important for protection. Recent results suggest that a substantial portion of the T cell response to infection is focused in non-lymphoid tissues. Furthermore, anatomic localization appears to define phenotypic and functional heterogeneity among antigen-specific memory T cell populations.