Hypothermia is a thermoregulatory response to systemic inflammation that is often regarded as maladaptive to the host. However, rodents show regulated hypothermia (that is, a selection of cool ambient temperature) during systemic inflammation that correlates with enhanced survival, supporting an adaptive value to this response. The mechanisms regulating hypothermia are not fully understood, but cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukins (ILs) and interferon-gamma have been shown to induce or modulate hypothermia. A review of the literature suggests that TNF-alpha functions as an endogenous cryogen (i.e., induces hypothermia), whereas IL-10 modulates TNF-alpha production and/or release as a mechanism of hypothermia attenuation. IL-1beta and IL-6 are typically regarded as endogenous pyrogens, but may induce hypothermia during viral and bacterial inflammation. A role for endogenous IFN-gamma in hypothermia has not been demonstrated, but injection of this cytokine potentiates hypothermia through augmented production of other cytokines. It is clear that additional research is required in this area. Suggested areas for future research include a determination of the final mediator of hypothermia and its specific anatomical site of action as well as the role of cytokines in the regulation of hypothermia under non-inflammatory conditions.