The profound anti-inflammatory effects of glucocorticoids in drug therapy are reflected in the effects in vivo of endogenous glucocorticoids produced by the adrenals. The production of adrenal glucocorticoids is driven by the hypothalamus and pituitary, which in turn are responsive to circulating products of the inflammatory response, especially cytokines. That inflammation can drive the production of anti-inflammatory glucocorticoids denotes the hypothalamic-pituitary-adrenal (HPA)-immune axis as a classic negative feedback control loop. Defects in HPA axis function are implicated in susceptibility to, and severity of, animal models of rheumatoid arthritis (RA), and are hypothesized to contribute to the human disease. In this paper, data supporting the concept of the HPA axis as a regulator of the inflammatory response in animal models of arthritis are reviewed, along with data from studies in humans. Taken together, these data support the hypothesis that the HPA axis provides one of the key mechanisms for inhibitory regulation of the inflammatory response. Manipulation of HPA axis-driven endogenous anti-inflammatory responses may provide new methods for the therapeutic control of inflammatory diseases.