Accumulating evidence suggests that RA is a T-cell-mediated autoimmune disease. Early attempts at disease modulation using strategies such as CD4 mAbs were severely hampered by a lack of biomarkers of autoreactivity. Recently, however, co-stimulation blockade has emerged as an effective treatment for RA. Alongside a greatly improved mechanistic understanding of immune regulation, this has rekindled hopes for authentic and robust immune programming. The final pieces of the jigsaw are not yet in place for RA but, in other disciplines, emerging treatment paradigms such as non-mitogenic anti-CD3 mAbs, autoantigenic peptides and even cellular therapies are providing hope for a future in which immunopathology can be specifically and vigorously curtailed.