Abstract: Corticosteroids (CSs) have potent immunosuppressive effects and are commonly used to treat a range of immunological and inflammatory diseases such as rheumatoid arthritis (RA). These effects are mediated by the ability of CSs to modulate gene expression. CSs act by binding to the CS receptor (CR), which exists as α and β isoforms. Only CRα binds CS. CRβ functions as an endogenous inhibitor of CS and is expressed in several tissues. The CS/CRα complex binds to the glucocorticosteroid response element in the nucleus and also interferes with AP‐1 and NF‐κB binding. Thus, CSs inhibit the transcription of AP‐1 and NF‐κB inducible genes, such as interleukin (IL)‐2, IL‐6, IL‐8, IL‐1β, and tumor necrosis factor (TNF) α, as well as T‐cell proliferation. In clinical practice, a proportion of RA patients do not respond adequately to CS therapy. On this basis, RA patients can be divided on clinical grounds and on the ability of CSs to inhibit concanavalin A (conA)‐induced peripheral blood T‐cell proliferation in vitro into CS‐sensitive (SS) and CS‐resistant (SR) subgroups. The in vitro defined SS and SR subgroups correlate with the clinical responses to CS therapy. The mechanisms of the SR in RA patients remain unknown but may include the following: dysregulation of CRα function, alterations in the intracellular signaling mechanisms and/or utilization of various other cellular activation pathways, perturbations of the cytokine milieu, and inhibition of lipocortin. In SR subjects, CSs fail to significantly inhibit conA‐induced IL‐2 and IL‐4 secretion and LPS‐induced IL‐8, IL‐1β secretion in vitro. CS therapy fails to reduce the circulating levels of IL‐8, IL‐1β, and TNFα in SR RA patients. Peripheral blood mononuclear cells (PBMCs) from SR significantly overexpress activated NF‐κB and IκBα. In vitro CSs fail to significantly inhibit conA‐induced NF‐κB activation in PBMCs from SR RA patients. Our preliminary observations show enhanced CRβ expression by PBMCs from SR RA patients. It is most likely that other molecular mechanisms such as enhanced AP‐1 expression are involved, and we currently are investigating such possibilities.