Rheumatoid arthritis (RA) is a chronic inflammatory disease and its exact cause and pathophysiological process remain unclear. Fibroblast-like synoviocytes, macrophages and T lymphocytes are considered to be the major contributors in the pathophysiological process of RA; however, an increasing number of papers have drawn attention to the potential role of mast cells (MCs) in the process. In an animal model of RA, we reported an increase in MC numbers in the arthritic region, which agreed with the observation in human RA. In addition, a good correlation between the number of MCs and the development of disease was observed. However, there has been little experimental or clinical evidence of the beneficial effects of the modification of MC activity on the pathogenesis of RA and this is the weak point of the hypothesis. We therefore studied the effects of a MC-stabilizing compound, cromoglicate lisetil (CL), which is an orally deliverable prodrug of cromolyn sodium, on the RA disease model. The MC-stabilizer had efficacy in a mouse model. The beneficial effects of CL in this animal model further suggested the contribution of MCs in the pathophysiological process of RA. Concerning the contributive mechanism of MC on the pathogenesis of RA, our results using a disease model suggested that activation of MC chymase and matrix metalloproteinases might be involved. MC is now considered to be one of the targets of RA treatment.