Ageing has been associated with immunological changes (immunosenescence) that resemble those observed following chronic stress or glucocorticoid (GC) treatment. These changes include thymic involution, lower number of naïve T cells, reduced cell-mediated immunity, and poor vaccination response to new antigens. It follows that immunosenescence could be associated with changes of peripheral GC levels. Indeed, when compared with young subjects, healthy elders are more stressed and show activation of the hypothalamus–pituitary–adrenal (HPA) axis. However, both beneficial and undesirable effects of GCs ultimately depend on the target tissue sensitivity to these steroids. Recent data indicate that peripheral lymphocytes from elders respond poorly to GC treatment in vitro. The present review summarizes recent findings which suggest that immunosenescence may be closely related to both psychological distress and stress hormones. Furthermore, chronically stressed elderly subjects may be particularly at risk of stress-related pathology because of further alterations in GC-immune signalling. Finally, the neuroendocrine hypothesis of immunosenescence is finally reconsidered in which the age-related increase in the cortisol/DHEA ratio is major determinant of immunological changes observed during ageing.