The hypothalamic-pituitary-adrenal (HPA) axis plays an important immunomodulatory role during viral infection. Activation of the HPA axis ultimately leads to elevated plasma levels of glucocorticoid (GC) hormones with the ability to mediate adaptive behavioral, metabolic, cardiovascular and immune system effects. In this review, we focus on the modulation of anti-viral immunity and viral pathogenesis by the HPA axis.