In anxiety research, the search for a model with sufficient clinical predictive validity to support the translation of animal studies on anxiolytic drugs to clinical research is challenging. The stress-induced hyperthermia (SIH) model studies the body temperature increase in response to acute stress which is mediated by the autonomic nervous system. This SIH response occurs in all mammals including humans, is easy to measure, reproducible and stable over time. The SIH paradigm has proven to possess excellent predictive validity, and various anxiolytic drugs have been shown to dose-dependently reduce the SIH response, including GABAA-receptor (subunit) agonists, 5-HT 1A receptor agonists, mGlu5 receptor antagonists and CRF receptor antagonists. Therefore, the SIH model is a simple and attractive paradigm to study putative anxiolytic drug properties as well as the effects of genetic or brain manipulations. In the SIH procedure, drugs are injected 60 minutes before the actual stressor, consisting of a manual rectal temperature measurement (T 1). After 10 minutes, a second manual rectal temperature measurement is taken (T 2), which represents the stress-induced body temperature. The SIH (ΔT) response is the difference between T 2 and T 1 (ΔT=T 2-T 1). As drugs might exert intrinsic effects on the basal body temperature (measured via T 1), the SIH response has to be interpreted in the context of absolute body temperatures. Mice can be repeatedly used (up to a year) if tested once a week because the SIH response remains very stable over such elongated periods. Animals can be socially housed except for the actual testing day (starting the day before until immediately after the procedure) when mice have to be singly housed. © 2009 Humana Press.