Slow-acting anti-rheumatic drugs exhibit a number of similar properties in treated patients that suggest that they may have a common mode of action in rheumatoid arthritis. In vitro evaluation of drug action suggests that each of the slow-acting agents possesses immunosuppressive activity that may explain its therapeutic efficacy in rheumatoid arthritis. Even though these agents appear to be able to suppress immune responses, the site of action of these agents differs. Thus, gold compounds and the antimalarials suppress the activity of mononuclear phagocytes, whereas D-penicillamine and other thiol-containing slow-acting agents inhibit the activity of helper T cells. These agents may therefore be effective by interfering with various specific aspects of the immunologic reactivity that drives the chronic inflammation of rheumatoid arthritis.