While new anti-cytokine disease-modifying anti-arthritic drugs for rheumatoid arthritis have been designed via mechanistic approaches, the mechanism of action of a number of more established disease-modifying anti-arthritic drugs has not been elucidated. In the case of d-penicillamine and sodium aurothiomalate, the key structural feature appears to be a free thiol group. However, the role thiol groups play in the therapeutic efficacy of these drugs has not been defined. A number of lines of evidence have demonstrated increased generation of reactive aldehydes and the associated depletion of free thiol pools in rheumatoid arthritis. These observations have led to the suggestion that reactive aldehydes may be the ultimate mediators of cell destruction in rheumatoid arthritis joints. Our data clearly demonstrate that thiol-containing disease-modifying anti-arthritic agents both directly sequester reactive aldehydes and augment intracellular thiol pools, which also can buffer increased aldehyde load and oxidative stress. These data are consistent with clinical data that penicillamine lowers synovial aldehyde levels and augments plasma thiols. We suggest that these actions are the pivotal mechanism of action of thiol-containing disease-modifying anti-arthritic drugs. Understanding the mechanism of action of these drugs provides the opportunity for the design of more potent and safer thiol drug candidates.