Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis has been well-described in mood disorders. Hypercortisolaemia, which has been attributed to a breakdown in glucocorticoid-receptor-mediated negative feedback mechanisms within the HPA axis, may be central to the pathogenesis of both the depressive symptoms and the cognitive deficits, which characterise severe mood disorders. Strategies to normalise glucocorticoid receptor (GR) function, and thus restore HPA functional integrity, have been the focus of recent research. Preliminary preclinical and clinical studies report encouraging results which suggest that lowering circulating cortisol levels, by up-regulating GRs, may have therapeutic efficacy in terms of improvements in depressive symptoms and cognitive functioning.