Glucocorticoids have a profound effect on the immune system and also on the HPA axis. Present insights into these mechanisms are discussed. Glucocorticoid resistance and clinical efficacy in the treatment of RA are reviewed. There is growing evidence for a positive effect of low-dose glucocorticoids on the retardation of erosive joint damage. Side effects of glucocorticoids on bone are now better controlled. Some guidelines to optimize glucocorticoid therapy in RA are given regarding dosage, timing, managing of side effects, and (new) types of glucocorticoids.