Although traditional disease modifying and biological response modifying agents are very useful in controlling disease activity, limiting disease progression, and improving function in patients with rheumatoid arthritis (RA), very few patients achieve full remission from treatment with these medications either when given alone or in combination. The combination of methotrexate (MTX) and the biologic agents appears to provide the highest level of response that is presently achievable. A contributory factor to the limited benefit from such regimens in some patients is that patients are unable to continue these medications, either because of lack of efficacy or adverse events. As even the most effective currently available interventions are not ideal in all patients, the search for new therapies -- which may be able to improve on the best possible clinical effect achievable to date -- is therefore necessary, desirable, and justified. One approach to new treatment paradigms for RA is to evaluate the role of B cells in RA and the effect of targeted B cell therapy on clinical outcome, based on a sound rationale and encouraging emerging clinical evidence. This approach will be examined in this and the following articles.