The complexity of the immune system, exemplified by the pleiotropic effects of many cytokines and the redundancy of regulatory networks controlling immune responses, suggests that single therapeutic interventions will offer transient or less than clinically meaningful benefit. Theoretically, combination therapy using 2 or more biologic agents will modulate important symptomatic and objective manifestations of rheumatoid arthritis (RA). Data from animal models suggest that use of biologic agents in combination can be synergistic and may alter the severity and course of disease. Although combinations of biologic agents have yet to be used in human disease, successful examples employing immunosuppressive agents exist: cyclosporin (CsA) with methotrexate in patients with persistent active RA, as well as azathioprine and/or mycophenolate mofitil with CsA in organ transplantation and acute graft rejection. There are many arguments against the use of combination biologic therapies including acute infusion related toxicities, infection, malignancy, autoimmune manifestations, and expense. While caution dictates that phase I-II clinical trials be performed in patients with longstanding, refractory disease, subsequent trials should be conducted in patients with earlier, more responsive disease. Successful combination biologic therapies must afford sufficient duration of benefit (at least 6, preferably 12 months), cost comparable to approved 2nd line agents, ease of treatment, and an acceptable safety profile.