Corticotropin-releasing factor (CRF) and its family of ligands are key regulators of energy balance. These ligands function via activation of their two receptors, CRFR1 and CRFR2. CRFR1 has been shown to be the dominant receptor in activation of the hypothalamic-pituitary-adrenal axis in response to stress as well as a key mediator of anxiety in the limbic system. To specifically examine the role of CRFR2 in energy balance, mice deficient for CRFR2 were exposed to physiological perturbations of homeostasis, including high-fat diet, repeated cold stress, and glucose and insulin challenges, and their responses measured. While on a high-fat diet, CRFR2-mutant mice consumed substantially more food and maintaining the same weight but had significantly lower body fat and lower plasma lipids than their wild-type littermates. These mice were also less inclined to develop diet-induced insulin resistance and more sensitive to changes in plasma glucose, indicating increased insulin sensitivity. Following repeated cold stress, mutant mice had significantly lower body fat and a transient reduction in feed efficiency, despite similar body weights, suggesting a possible preference for fat as an energy substrate. Elevated levels of uncoupling protein-1 in brown adipose tissue as well as smaller white and brown adipocytes from CRFR2-mutant mice were indications of possible increased sympathetic tone. These results demonstrate that CRFR2 plays a critical role in regulation of energy expenditure and is important for responses to homeostatic challenges.