The interactions between the immune system and HPA axis may be characterized by a circuit which includes; (i) activation of the HPA axis and initiation of the stress response which, in term, has immunomodulating properties; (ii) a feedback mechanism derived from the immune system which regulates the HPA axis. Over the past few years, it has become evident that the adrenal gland, itself, as the main effector organ of the HPA axis, is a major site for both the synthesis and action of numerous cytokines. In addition to the cytokine mediated activation of adrenal regulation there are cytokine independent cell-cell mediated immune-adrenal interactions. The nature of this immune-endocrine crosstalk is implicated in adrenal dysfunction and disease. During inflammatory and autoimmune disorders including sepsis, inflammatory bowel disease and rheumatoid arthritis, the immune-adrenal crosstalk becomes more critical in maintaining an adequate adrenal stress response.