Glucocorticoids (GCs) exert profound influences on many physiologic functions by virtue of their diverse roles in growth, development, and maintenance of homeostasis. We previously created a novel gain of function in the human glucocorticoid receptor (hGR), hGRM604L, which is active at GC concentrations 5-10-fold lower than wild-type GR. To gain a greater insight into GC physiology in vivo, we inserted this mutant GR (GRM610L in mice) into mice via homologous recombination. Mice expressing the allele are phenotypically normal with respect to GC function. However, corticosterone levels, ACTH levels, and adrenocortical size are markedly reduced, suggesting they are phenotypically normal because the mutant GR alters the basal regulation of the hypothalamic-pituitary-adrenal axis. We demonstrate via physiologic and immunologic studies that GRM610L mice have increased sensitivity to GCs in vivo. Sensitivity to the actions of endogenous GCs may be an important factor underlying the development of many human diseases including hypertension, obesity, and diabetes. Our model may provide a new and powerful tool for the study of GC physiological and pathological processes in vivo.