The current report summarized animal models of heatstroke experimentation that advance our current knowledge of therapeutic effects on cerebrovascular dysfunction, hypercoagulable state and/or systemic inflammation with various agents in the setting of heatstroke. This was a narrative review of selected published primary basic literature from MEDLINE for 1973-2006. It was found that rodents shared with humans almost the same heatstroke reactions such as hyperpyrexia, hypotension, hyperventilation, pulmonary edema, hepatic and renal failure, hypercoagulable state, metabolic acidosis, systemic inflammation, and cerebral ischemia, injury and dysfunction. Therefore, the rodent model would allow testing of new therapeutic strategies for heatstroke. It was found that brain cooling produced by infusion of cold (4°C) normal saline via the jugular vein or whole body cooling improved survival during heatstroke by reducing cerebrovascular dysfunction, multiple organ failure, systemic inflammation and hypercoagulable state. However, even under the absence of brain or whole body cooling, these heatstroke reactions still could be reversed by treating with the following agents: (1) free radical scavengers; (2) human recombinant protein C: (3) platonin; (4) hyperbaric oxygen; (5) hydroxyethyl starch, hypertonic solution, or human albumin; (6) glucocorticoids; (7) interleukin-1 receptor antagonists; (8) L-arginine; (9) estrogen; and (10) human umbilical cord blood cells or CD +34 cells. Before initiation of heat stress, prior manipulations with one of the following measures were found to be able to protect against heatstroke syndromes: (1) systemic delivery of inducible nitric oxide synthase inhibitors, mu-opioid receptor antagonists, endothelin-1A receptor antagonists, dopaminergic or serotoninergic nerve depletor or receptor antagonists, or glutamate receptor antagonists; or (2) heat shock protein 72 preconditioning.