The role of combination therapy in rheumatoid arthritis (RA) is increasing with the development of new treatment modalities. Past combinations of slow-acting anti-rheumatic drugs resulted in either excessive side-effects or lack of efficacy over single-agent therapy. However, refined methodology and a better understanding of the mechanism of action of newer agents have led to improved combinations, which appear more promising. In particular, in a 6 month, randomized, double-blind trial, the combination of cyclosporin (CyA) with methotrexate was found to be more efficacious than methotrexate alone, providing enhanced clinical benefit, without evidence of increased adverse events. The mean final dose of 2.97 mg/kg per day CyA in combination was lower than that required for CyA monotherapy. Further, a new formulation of CyA, with improved bioavailability, should provide enhanced efficacy and an acceptable safety profile, not only as monotherapy but also in combination with agents such as methotrexate. These developments offer new hope to patients with progressive RA, which is unresponsive to conventional therapy.