Experimental evidence and clinical experience suggest that mild hypothermia protects numerous tissues from damage during ischemic insult. However, the extent to which hypothermia becomes a valued therapeutic option will depend on the clinician's ability to rapidly reduce core body temperature and safely maintain hypothermia. To date, general anesthesia is the best way to block autonomic defenses during induction of mild-to-moderate hypothermia; unfortunately, general anesthesia is not an option in most patients likely to benefit from therapeutic hypothermia. Induction of hypothermia in awake humans is complicated by both the technical difficulties related to thermal manipulation and the remarkable efficacy of thermoregulatory defenses, especially vasoconstriction and shivering. The most effective thermal manipulation devices are generally invasive and, therefore, more prone to complications than surface methods. In an effort to inhibit thermoregulation in awake humans, several agents have been tested either alone or in combination with each other. For example, the combination of meperidine and buspirone has already been applied to facilitate induction of hypothermia in human trials. However, pharmacological induction of thermoregulatory tolerance to cold without excessive sedation, respiratory depression, or other serious toxicity remains a major focus of current therapeutic hypothermia research.