The hypothalamic-pituitary-adrenal (HPA) axis response in sepsis remains to be elucidated. Apart from corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol, many other neuroendocrine factors participate in the regulation of HPA stress response. The HPA response to acute and chronic illness exerts a biphasic profile. Tissue corticosteroid resistance may also play an important role. All of these add to the complexity of the concept of 'relative adrenal insufficiency' and may account for the difficulty of clinical diagnosis and for the conflicting results of corticosteroid replacement therapy in severe sepsis/septic shock. The study by Lesur and colleagues expands our understanding of the mechanism, and further study of HPA stress response is warranted.