While glucocorticoids are widely used in the suppression of immune-inflammatory diseases, much remains unknown about the contribution of endogenous adrenal glucocorticoids to inflammatory regulation. It is now well understood that glucocorticoids are increased by inflammatory stress and provide for responsive limitation of inflammation. It is self-evident that the immune response in healthy animals takes place in a milieu characterised by background levels of glucocorticoids. It is less well appreciated, however, that basal levels of glucocorticoids may in fact be a requirement for a normal immune response. In fact, extensive data exist supporting the hypothesis that glucocorticoids interact with the immune-inflammatory system in a biphasic, concentration dependent fashion. No mechanistic explanation for this apparent paradox has previously existed. Recently, the cytokine macrophage migration inhibitory factor (MIF), while possessing pleiotropic pro-inflammatory properties, has been demonstrated to be glucocorticoid-inducible. This observation has the potential to explain key aspects of the biphasic regulation of inflammatory response by endogenous glucocorticoids.