Salivary cortisol sampling has confirmed the presence of increased cortisol secretion in depression and has also revealed that some aspects of hypothalamo-pituitary-adrenal (HPA) axis disturbance have trait-like characteristics that may predict the risk of future illness. Persistent hypersecretion of cortisol in individuals vulnerable to depression also has implications for the medical co-morbidities associated with mood disorder. Pharmacological treatments targeted at the HPA axis represent a novel approach to the management of depression and its complications; however, a better understanding of the molecular basis of HPA axis dysfunction in depressed patients will be needed before this promise can be fulfilled.