Acute respiratory distress syndrome (ARDS) is a disease of multifactorial etiology characterised by rapid development of severe diffuse and nonhomogenous inflammation of the pulmonary lobules causing life-threatening hypoxaemic respiratory failure. The current authors tested a therapeutic intervention on a previously defined pathophysiological model of ARDS. The model was defined by investigating, during the natural history of ARDS, the relationship among the three fundamental elements of a disease process pathogenesis, structural alterations, and functional consequences. In these studies, the present authors provided biological and morphological evidence indicating that ARDS patients failing to improve after 1 week of mechanical ventilation (unresolving ARDS) have intense and protracted (dysregulated) pulmonary and systemic inflammatory and neo-fibrogenetic activity. Nuclear factor-kappaB and the glucocorticoid receptor have diametrically opposed functions in regulating inflammation. This chapter will review recent data indicating that poor outcome in acute respiratory distress syndrome might be related in part to failure of the activated glucocorticoid receptors to downregulate the transcription of inflammatory cytokines despite elevated levels of circulating cortisol. In a small randomised study of patients with unresolving acute respiratory distress syndrome, the current authors have shown that prolonged glucocorticoid supplementation improved all aspects of glucocorticoid receptors function and enhanced glucocorticoid-mediated anti-inflammatory action by interfering with nuclear factor-kappaB activation.