It would be extremely beneficial if one could harness natural, endogenous, health-promoting defense mechanisms to fight disease and restore health. The psycho-physiological stress response is the most under-appreciated of nature's survival mechanisms. Here we show that acute stress experienced before primary immunization induces a long-lasting increase in immunity. Compared to controls, mice restrained for 2.5 hours before primary immunization with keyhole limpet hemocyanin (KLH) show a significantly enhanced immune response when re-exposed to KLH nine months later. This immuno-enhancement is mediated by an increase in numbers of memory and effector helper T cells in sentinel lymph nodes at the time of primary immunization. Further analyses show that the early stress-induced increase in T cell memory may stimulate the robust increase in infiltrating lymphocyte and macrophage numbers observed months later at a novel site of antigen re-exposure. Enhanced leukocyte infiltration may be driven by increased levels of the Type-1 cytokines, IL-2 and IFN-, and TNF-, observed at the site of antigen re-exposure in animals that had been stressed at the time of primary immunization. In contrast, no differences are observed in Type-2 cytokines, IL-4 or IL-5. Given the importance of inducing long-lasting increases in immunological memory during vaccination, we suggest that the neuroendocrine stress response is nature's adjuvant that could be psychologically and/or pharmacologically manipulated to safely increase vaccine efficacy. These studies introduce the novel concept that a psycho-physiological stress response is nature's fundamental survival mechanism that could be therapeutically harnessed to augment immune function during vaccination, wound healing or infection.