An increase in body temperature in association with inflammation or infection has been evolutionarily conserved in all cold and warm-blooded vertebrates and even in several invertebrates thus far examined. This change in temperature is strongly correlated with survival from infection in many animal models. Although the means by which body temperature is increased and maintained differs between cold- versus warm-blooded species, there are strong similarities in terms of the magnitude of temperature change and its duration. Despite these intriguing observations and significant biological sequelae, temperature manipulation is rarely considered in the context of most experimental immunological investigations. We have hypothesized that the thermal microenvironment plays a critical role in regulating events in the immune response and that an increase in ambient temperature can serve as a natural trigger or "danger signal" to the immune system. To examine the direct effects of fever-like temperatures on immunological parameters, we have designed and characterized protocols for performing whole body heating of mice and humans in vivo, and heating of cultured cells in vitro. Our studies have now progressed to the development of therapeutic uses of fever-range hyperthermia in combination with other therapies. This chapter describes the experimental procedures that have been developed for these studies and summarizes several of the immunologically relevant effects that we have noticed following mild heat treatments in vivo and in vitro.