Recent research on rheumatoid arthritis (RA) has broadened our understanding of this disease, and mediators of the disease process have been identified as potential therapeutic targets. A series of novel agents have been developed specifically targeting these mediators and are collectively referred to as biologic response modifiers or biologic agents. A number of these agents have been introduced into clinical practice or are currently in clinical trials. Agents that have been approved include 2 monoclonal antibodies and a receptor fusion protein, all of which target tumor necrosis factor (TNF), as well as an inhibitor of interleukin-1 (IL-1). Other areas that are currently being investigated are new methods of blocking TNF and other cytokines, including IL-1 and IL-6. Emerging data also suggest that both T and B cells have critical roles in the pathogenesis of RA and could provide rational targets for therapy. Additionally, the role of adhesion molecules in RA continues to expand, and several agents have been proposed as potential therapies. These rapid advances in our understanding of RA and their implications for rationally targeted therapies are reviewed.