Major advances in the therapy of RA will likely require future scientific breakthroughs in the understanding of pathophysiology. That is not to suggest that clinical investigations should be put on hold while the entire focus of research shifts to the laboratory bench. Clinical studies of very early RA, including early treatment interventions, would appear to be of major importance. However, better characterization of the early clinical course and identification of pathologic markers of progressive disease are needed before formal randomized treatment studies of early disease can be initiated. The entire role of aggressive management, particularly with combination chemotherapy, at any stage of RA is in desperate need of answers. In clinical practice it would appear that combination chemotherapy is widely used, often as a last resort in treatment resistant patients who have failed conventional therapies. The published clinical studies would seem to support, but certainly not prove, a valuable potential role for combination chemotherapy in this setting. Moreover, the studies seem to indicate some increased risk of drug toxicities, the limitations of which are not readily apparent for most combinations. Based on the successes observed in these patients that are very difficult to treat, the possibility of a more fundamental role of combination chemotherapy in treatment of the disease has been advocated. These questions need to be resolved by well designed, randomized controlled trials. There is an urgent need to do the trials soon before combination chemotherapy gains an even stronger foothold in therapy.