Glucocorticoid hormones exert a wide spectrum of metabolic and immunological effects. They function through the glucocorticoid receptor, a member of the nuclear receptor superfamily. Glucocorticoids are particularly effective as anti-inflammatory agents but often cause severe side effects. The structure of the ligand-binding domain of the glucocorticoid receptor has now been elucidated, and a series of studies have shown that even subtle changes to the ligand structure alter the final conformation of the ligand-receptor complex, with consequences for both protein recruitment and the function of the receptor. This has led to concerted efforts to find selective ligands for the glucocorticoid receptor that preserve the beneficial anti-inflammatory activity but reduce the side-effect profile. The direct health-care benefits of such a simple, safe, orally active agent targeting the underlying inflammatory process in, for example, rheumatoid arthritis would be considerable in terms of reduced patient suffering; furthermore, the indirect benefits in terms of reducing the costs of therapeutic delivery and preventing loss of productivity would be even greater.