The need for treatment of obesity and obesity-related diseases, such as type 2 diabetes, has been intensified by the epidemic rise of obesity. Recent advances make possible continuous monitoring of metabolically relevant functions in animals to identify novel thermogenic and anorectic compounds. This unit describes non-invasive in vivo calorimetric assessment of energy expenditure using measurements of oxygen consumption and carbon dioxide production, complemented by telemetric monitoring of body core temperature and locomotor activity in mice and rats. Reference compounds are used to illustrate the determination of substance-specific parameters, such as the dose that produces the half-maximal effect (ED(50)), the maximal effect, as well as the time of onset and duration of compound action. Indirect calorimetry performed at different temperatures provides information on several other well-defined parameters, including resting metabolic rate, basal metabolic rate, lower critical temperature, temperature sensitivity, defended body temperature, and respiratory quotient.