Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis is common in patients with major depression. A recent study demonstrates that reduced expression of the glucocorticoid receptor in mice causes depression-like behaviors and HPA axis dysfunction following stressor exposure. This model offers a novel system for the study of the pathophysiology that underlies depression-like behaviors. It also adds to the growing evidence that implicates glucocorticoid receptor dysfunction in depression.