Depression-related cognitive impairment (DRCI) is a condition which despite its initial treatment response, shows a progressive deterioration. No consistent therapeutic strategies have been proposed to combat this condition. This may be due to a reluctance to treat the cognitively impaired, a failure to recognise the deleterious prognosis or a poor understanding of the likely pathogenesis. Increasing evidence implicates the hypothalamo-pituitary-adrenal (HPA) axis as a key neurobiological determinant of the presentation and course of depression-induced cognitive decline. By utilising agents which control central glucocorticoid hyperactivity over a sustained period, whilst avoiding those agents which may compromise cognitive abilities, there exists a pharmacological strategy which may minimise the morbidity of cognitive impairment related to depressive illness.