The therapy of rheumatoid arthritis has been revolutionised by advances in the understanding of disease at a cellular and molecular level accompanied by the technology to target specific mediators of disease. Proposed therapeutic targets from in vitro and animal models however have frequently resulted in unexpected outcomes in clinical trials. These have included have included cytokines, chemokines, the T cell receptor trimolecular complex, T cells and B cells. The most successful strategies have resulted from a close dialogue between clinical and laboratory work. The key stages in the development of these agents and remaining unanswered questions are reviewed.