The pathogenesis of rheumatoid arthritis remains unknown. Disease modifying anti-rheumatic drugs are commonly used to treat rheumatoid arthritis patients. Their use in rheumatoid arthritis was discovered serendipitously and their modes of action remain unknown. This article reviews current hypotheses on the mechanisms of action of established DMARDs. Most of them have anti-inflammatory properties and some are immunomodulators. We also discuss a number of novel agents which are potential new DMARDs.